Impact of nutritional status on vaccine-induced immunity in children living in South Africa: Investigating the B-cell repertoire and metabolic hormones.

OBJECTIVES: We explored the role of metabolic hormones and the B-cell repertoire in the association between nutritional status and vaccine responses. METHODS: In this prospective cohort study, nested within a larger randomized open-label trial, 211 South African children received two doses of measles vaccine and two or three doses of pneumococcal conjugate vaccine (PCV). Metabolic markers (leptin, ghrelin and adiponectin) and distribution of B-cell subsets (n = 106) were assessed at 18 months of age. RESULTS: Children with a weight-for-height z-score (WHZ) ≤ -1 standard deviation (SD) at booster vaccination had a decreased mean serotype-specific PCV IgG response compared with those with WHZ > -1 and <+1 SD or WHZ ≥ +1 SD at 9 months post-booster (18 months of age). (Naive) pre-germinal center B-cells were associated with pneumococcal antibody decay between one to nine months post-booster. Predictive performance of elastic net models for the combined effect of B-cell subsets, metabolic hormones and nutritional status (in addition to age, sex, and randomization group) on measles and PCV vaccine response had an average area under the receiver operating curve of 0.9 and 0.7, respectively. CONCLUSIONS: The combined effect of B-cell subsets, metabolic hormones and nutritional status correlated well with the vaccination response for measles and most PCV serotypes. CLINICALTRIALS: gov registration of parent studies: NCT02943902 and NCT03330171.

Immunoglobulin A deficiency in children, an undervalued clinical issue.

Immunoglobulin A (IgA) is the principal antibody in secretions that bathe the gastrointestinal and respiratory mucosal surfaces and acts as an important first line of defense against invasion of pathogenic micro-organisms. The reported prevalence rate of complete IgA deficiency in healthy children ranges from 1:170 to 1:400, and as a solitary condition, it is often considered of limited clinical importance. However, patients with IgA deficiency can develop recurrent respiratory and gastrointestinal infections, as well as allergic and autoimmune diseases. In children referred for recurrent respiratory tract infections, the observed prevalence rate increases more than tenfold. This review discusses several aspects of IgA deficiency in children, including immunologic and microbiome changes in early childhood and the potential consequences of this condition in later life. It illustrates the importance of early identification of children with impaired IgA production who deserve appropriate clinical care and follow-up.

Activation of autophagy by FOXO3 regulates redox homeostasis during osteogenic differentiation.

Bone remodeling is a continuous physiological process that requires constant generation of new osteoblasts from mesenchymal stem cells (MSCs). Differentiation of MSCs to osteoblast requires a metabolic switch from glycolysis to increased mitochondrial respiration to ensure the sufficient energy supply to complete this process. As a consequence of this increased mitochondrial metabolism, the levels of endogenous reactive oxygen species (ROS) rise. In the current study we analyzed the role of forkhead box O3 (FOXO3) in the control of ROS levels in human MSCs (hMSCs) during osteogenic differentiation. Treatment of hMSCs with H2O2 induced FOXO3 phosphorylation at Ser294 and nuclear translocation. This ROS-mediated activation of FOXO3 was dependent on mitogen-activated protein kinase 8 (MAPK8/JNK) activity. Upon FOXO3 downregulation, osteoblastic differentiation was impaired and hMSCs lost their ability to control elevated ROS levels. Our results also demonstrate that in response to elevated ROS levels, FOXO3 induces autophagy in hMSCs. In line with this, impairment of autophagy by autophagy-related 7 (ATG7) knockdown resulted in a reduced capacity of hMSCs to regulate elevated ROS levels, together with a reduced osteoblast differentiation. Taken together our findings are consistent with a model where in hMSCs, FOXO3 is required to induce autophagy and thereby reduce elevated ROS levels resulting from the increased mitochondrial respiration during osteoblast differentiation. These new molecular insights provide an important contribution to our better understanding of bone physiology.

Adaptive immune response to whole cell pertussis vaccine reflects vaccine quality: A possible complementation to the Pertussis Serological Potency test.

Whole cell Bordetella pertussis (wP) vaccines are still used in many countries to protect against the respiratory disease pertussis. The potency of whole-cell pertussis vaccine lots is determined by an intracerebral challenge test (the Kendrick test). This test is criticized due to lack of immunological relevance of the read-out after an intracerebral challenge with B. pertussis. The alternative in vivo test, which assesses specific antibody levels in serum after wP vaccination, is the Pertussis Serological Potency test (PSPT). Although the PSPT focuses on a parameter that contributes to protection, the protective immune mechanisms after wP vaccination includes more elements than specific antibody responses only. In this study, additional parameters were investigated, i.e. circulating pro-inflammatory cytokines, antibody specificity and T helper cell responses and it was evaluated whether they can be used as complementary readout parameters in the PSPT to assess wP lot quality. By deliberate manipulation of the vaccine preparation procedure, a panel of high, intermediate and low quality wP vaccines were made. The results revealed that these vaccines induced similar IL-6 and IP10 levels in serum 4h after vaccination (innate responses) and similar antibody levels directed against the entire bacterium. In contrast, the induced antibody specificity to distinct wP antigens differed after vaccination with high, intermediate and low quality wP vaccines. In addition, the magnitude of wP-induced Th cell responses (Th17, Th1 and Th2) was reduced after vaccination with a wP vaccine of low quality. T cell responses and antibody specificity are therefore correlates of qualitative differences in the investigated vaccines, while the current parameter of the PSPT alone was not sensitive enough to distinguish between vaccines of different qualities. This study demonstrates that assessment of the magnitude of Th cell responses and the antigen specificity of antibodies induced by wP vaccination could form valuable complementary parameters to the PSPT.

In vitro innate immune cell based models to assess whole cell Bordetella pertussis vaccine quality: a proof of principle.

Lot release testing of vaccines is primarily based on animal models that are costly, time-consuming and sometimes of questionable relevance. In order to reduce animal use, functional in vitro assays are being explored as an alternative approach for the current lot release testing paradigm. In this study, we present an evaluation of APC platforms assessing innate immune activation by whole cell Bordetella pertussis (wP) vaccines. Primary monocytes, monocyte-derived DC (moDC) and human monocyte/DC cell lines (MonoMac6 and MUTZ-3) were compared for their capacity to respond to wP vaccines of varying quality. To produce such vaccines, the production process of wP was manipulated, resulting in wP vaccines covering a range of in vivo potencies. The responses of MUTZ-3 cells and primary monocytes to these vaccines were marginal and these models were therefore considered inappropriate. Importantly, moDC and MonoMac6 cells responded to the wP vaccines and discriminated between vaccines of varying quality, although slight variations in the responses to wP vaccines of similar quality were also observed. This study provides a proof of principle for the use of in vitro APC platforms as part of a new strategy to assess wP vaccine lot consistency, though careful standardisation of assay conditions is necessary.

Pharmacokinetics of anti-tuberculosis drugs in Venezuelan children younger than 16 years of age: supportive evidence for the implementation of revised WHO dosing recommendations.

OBJECTIVES: The World Health Organization (WHO) recently issued revised first-line antituberculosis (anti-TB) drug dose recommendations for children, with dose increases proposed for each drug. No pharmacokinetic data are available from South American children. We examined the need for implementation of these revised guidelines in Venezuela. METHODS: Plasma isoniazid, rifampicin, pyrazinamide and ethambutol concentrations were assessed prior to and at 2, 4 and 8 h after intake of TB drugs by 30 TB patients aged 1-15 years. The effects of dose in mg/kg, age, sex, body weight, malnutrition and acetylator phenotype on maximum plasma drug concentrations (Cmax) and exposure (AUC0-24) were determined. RESULTS: 25 patients (83%) had an isoniazid Cmax below 3 mg/l and 23 patients (77%) had a rifampicin Cmax below 8 mg/l. One patient (3%) had a pyrazinamide Cmax below 20 mg/l. The low number of patients on ethambutol (n = 5) precluded firm conclusions. Cmax and AUC0-24 of all four drugs were significantly and positively correlated with age and body weight. Patients aged 1-4 years had significantly lower Cmax and AUC0-24 values for isoniazid and rifampicin and a trend to lower values for pyrazinamide compared to those aged 5-15 years. The geometric mean AUC0-24 for isoniazid was much lower in fast acetylators than in slow acetylators (5.2 vs. 12.0, P < 0.01). CONCLUSION: We provide supportive evidence for the implementation of the revised WHO pediatric TB drug dose recommendations in Venezuela. Follow-up studies are needed to describe the corresponding plasma levels that are achieved by the recommended increased doses of TB drugs.

Helminths and skewed cytokine profiles increase tuberculin skin test positivity in Warao Amerindians.

The immune regulatory mechanisms involved in the acquisition of Mycobacterium tuberculosis infection in children are largely unknown. We investigated the influence of parasitic infections, malnutrition and plasma cytokine profiles on tuberculin skin test (TST) positivity in Warao Amerindians in Venezuela. Pediatric household contacts of sputum smear-positive tuberculosis (TB) cases were enrolled for TST, chest radiograph, plasma cytokine analyses, QuantiFERON-TB Gold In-Tube (QFT-GIT) testing and stool examinations. Factors associated with TST positivity were studied using generalized estimation equations logistic regression models. Of the 141 asymptomatic contacts, 39% was TST-positive. After adjusting for age, gender and nutritional status, TST positivity was associated with Trichuris trichiura infections (OR 3.5, 95% CI 1.1-11.6) and low circulating levels of T helper 1 (Th1) cytokines (OR 0.51, 95% CI 0.33-0.79). Ascaris lumbricoides infections in interaction with Th2- and interleukin (IL)-10-dominated cytokine profiles were positively associated with TST positivity (OR 3.1, 95% CI 1.1-8.9 and OR 2.4, 95% CI 1.04-5.7, respectively). A negative correlation of QFT-GIT mitogen responses with Th1 and Th2 levels and a positive correlation with age were observed (all p < 0.01). We conclude that helminth infections and low Th1 cytokine plasma levels are significantly associated with TST positivity in indigenous Venezuelan pediatric TB contacts.

Neurobiology driving hyperactivity in activity-based anorexia.

Hyperactivity in anorexia nervosa is difficult to control and negatively impacts outcome. Hyperactivity is a key driving force to starvation in an animal model named activity-based anorexia (ABA). Recent research has started unraveling what mechanisms underlie this hyperactivity. Besides a general increase in locomotor activity that may be an expression of foraging behavior and involves frontal brain regions, the increased locomotor activity expressed before food is presented (food anticipatory behavior or FAA) involves hypothalamic neural circuits. Ghrelin plays a role in FAA, whereas decreased leptin signaling is involved in both aspects of increased locomotor activity. We hypothesize that increased ghrelin and decreased leptin signaling drive the activity of dopamine neurons in the ventral tegmental area. In anorexia nervosa patients, this altered activity of the dopamine system may be involved not only in hyperactivity but also in aberrant cognitive processing related to food.

Factors underlying diagnostic delay in tuberculosis patients in a rural area in Tanzania: a qualitative approach.

BACKGROUND: Diagnostic delay in patients with tuberculosis (TB) leads to ongoing TB transmission, higher mortality rates and increased patient and government health expenditure. Qualitative research focussed on patients' self-perceptions of disease and their care-seeking behaviour helps to guide health education programmes by providing us with the understanding of the knowledge, attitudes and practices that underlie diagnostic delay. PATIENTS AND METHODS: Semi-structured interviews with 28 recently diagnosed TB patients and four traditional healers were conducted. The interviews were audio-recorded and content analysis was performed. RESULTS: The median total delay was 188 days. The health provider delay (31 days) was longer than the patient delay (21 days) and the health system delay (26 days). The health system delay was longest in patients not being diagnosed at their first hospital visit and subsequently visiting other health care providers, mostly traditional healers. CONCLUSIONS: A poor knowledge of TB signs and symptoms and patients' beliefs about curses as the origin of diseases lead to delayed care-seeking at the hospital level in an area of North-Western Tanzania. Failure to identify TB cases by formal and non-formal health providers indicates that the education of both communities as well as health workers is essential in order to reduce diagnostic delays.

Are there species-universal categories in bird song phonology and syntax? A comparative study of chaffinches (Fringilla coelebs), zebra finches (Taenopygia guttata), and swamp sparrows (Melospiza georgiana).

Previous studies of learned bird song have suggested the existence of species-universal patterns in song organization: clear clusters in produced songs that do not vary within a species. Here the authors combine a computational method of comparing songs with statistical methods of assessing cluster structure to investigate this issue in a more quantitative manner. The authors first analyze song phonology and then examine song syntax at a population level in 3 species with very different song structure: chaffinches (Fringilla coelebs), zebra finches (Taenopygia guttata), and swamp sparrows (Melospiza georgiana). The authors used a dynamic time-warping algorithm to compare song elements, which closely matched the judgments of human observers. Clustering tendency and validation statistics showed that broad phonological categories existed in all 3 species, but these categories explained no more than half of the overall phonological variation. The authors developed a novel statistic to assess syntactical structure, which indicated that element transitions were not randomly distributed. In the clearest case, in chaffinches, this could be explained by syllables being linked to certain positions within the song. These results demonstrate measures of song organization that can be applied across species, enhancing the potential of comparative studies.

Progress towards tuberculosis elimination: secular trend, immigration and transmission.

This study aimed to determine to what extent tuberculosis trends in the Netherlands depend on secular trend, immigration and recent transmission. Data on patients in the Netherlands Tuberculosis Register in the period 1993-2007 were matched with restriction fragment length polymorphism (RFLP) patterns of Mycobacterium tuberculosis isolates. Index patients were defined as patients with pulmonary tuberculosis whose isolates had RFLP patterns not observed in another patient in the previous 2 yrs. Among 8,330 patients with pulmonary tuberculosis the isolates of 56% of native and 50% of foreign-born patients were clustered. Of these, 5,185 were included in detailed analysis: 1,376 native index patients, 2,822 foreign-born index patients and 987 secondary cases within 2 yrs of diagnosis of the index case. The incidence of native and foreign-born index patients declined by 6% and 2% per year, respectively. The number of secondary cases per index case was 0.24. The decline of native cases contributed most to the overall decline of tuberculosis rates and was largely explained by a declining prevalence of latent infection. Tuberculosis among immigrants was associated with immigration figures. Progress towards elimination of tuberculosis would benefit from intensifying diagnosis and treatment of latent infection among immigrants and global tuberculosis control.

deFOG--A real time system for detection and unfreezing of gait of Parkinson's patients.

Freezing of gait (FOG) is a common complication in movement disorders, typically associated with the advanced stages of Parkinson's disease. Auditory cues might be used to facilitate unfreezing of gait and prevent fall related injuries. We present a wearable, unobtrusive system for real-time gait monitoring, which consists of an inertial wearable sensor and wireless headset for the delivery of acoustic cues. The system recognizes FOG episodes with minimum latency and delivers acoustic cues to unfreeze the gait. We present design of a system for the detection and unfreezing of gait (deFOG), and preliminary results of the feasibility study. In a limited test run of 4 test cases the system was able to detect freezing of gait with average latency of 332 ms, and maximum latency of 580 ms.

The rubber hand illusion in action.

In the well-known rubber hand illusion (RHI), watching a rubber hand being stroked while one's own unseen hand is synchronously stroked, induces a relocation of the sensed position of one's own hand towards the rubber hand [Botvinick, M., & Cohen, J. (1998). Rubber hands 'feel' touch that eyes see. Nature, 391(6669), 756]. As one has lost the veridical location of one's hand, one should not be able to correctly guide one's hand movements. An accurate representation of the location of body parts is indeed a necessary pre-requisite for any correct motor command [Graziano, M. S. A., & Botvinick, M. M. (1999). How the brain represents the body: Insights from neurophysiology and psychology. In D. Gopher, & A. Koriat (Eds.), Attention and performance XVII-Cognitive regulation of performance interaction of theory and application (pp. 136-157)]. However, it has not yet been investigated whether action is indeed affected by the proprioceptive drift towards the rubber hand, nor has the resistance of visual capture in the RHI to new proprioceptive information been assessed. In the present two kinematic experiments, we show for the first time that action resists the RHI and that the RHI resists action. In other words, we show a dissociation between illusion-insensitive ballistic motor responses and illusion-sensitive perceptual bodily judgments. Moreover, the stimulated hand was judged closer to the rubber hand for the perceptual responses, even after active movements. This challenges the view that any proprioceptive update through active movement of the stimulated hand erases the illusion. These results expand the knowledge about representations of the body in the healthy brain, and are in line with the currently most used dissociation between two types of body representations so far mainly based on neuropsychological patients [Paillard, J. (1991). Knowing where and knowing how to get there. In J. Paillard (Ed.), Brain and space (pp. 461-481); Paillard, J. (1999). Body schema and body image: A double dissociation in deafferented patients. In G. N. Gantchev, S. Mori, & J.Massion (Eds.), Motor control, today and tomorrow (pp. 197-214)].

Fractal characteristics of human Parkinsonian neuronal spike trains.

Fractal analysis was applied to human pallidal neuronal spike trains recorded from patients with Parkinson's disease during ablative surgery of the internal segment of the globus pallidus. Fractal dynamics was quantified by computing the scaling exponent with the average wavelet coefficient approach. We observed fractal persistent correlation in the fluctuation of the interspike intervals of neuronal spike trains recorded in the internal segment of the globus pallidus both before and after the administration of dopamine agonist apomorphine. However, there was a significant increase in the scaling exponent during the "on" state after apomorphine administration as compared with the parkinsonian "off" state prior to apomorphine. In addition, we observed a statistically significant decrease in the average firing rate in the transition from the "off" to the "on" state. We conclude that robust fractal dynamics can be observed in single neurons in the human CNS, indicating that human neuronal dynamics of the internal segment of the globus pallidus are essentially a nonlinear and nonequilibrium process, with a long-range correlation or memory extending across many time scales. Accompanying the "on" state after apomorphine administration was an improvement in the long-range persistent correlation as compared with the more random dynamics in the "off" state. A scaling exponent signaling a breakdown or modification in long-range correlation in a single neuron may serve as a useful indicator of a dysfunctional network in the human CNS.

Hypothalamic neuropeptide expression following chronic food restriction in sedentary and wheel-running rats.

When rats are given access to a running-wheel in combination with food restriction, they will become hyperactive and decrease their food intake, a paradoxical phenomenon known as activity-based anorexia (ABA). Little is known about the regulation of the hypothalamic neuropeptides that are involved in the regulation of food intake and energy balance during the development of ABA. Therefore, rats were killed during the development of ABA, before they entered a state of severe starvation. Neuropeptide mRNA expression levels were analysed using quantitative real-time PCR on punches of separate hypothalamic nuclei. As is expected in a state of negative energy balance, expression levels of agouti-related protein (AgRP) and neuropeptide Y (NPY) were increased 5-fold in the arcuate nucleus (ARC) of food-restricted running ABA rats vs 2-fold in sedentary food-restricted controls. The co-regulated expression of AgRP and NPY strongly correlated with relative body weight and white adipose tissue mass. Arcuate expression of pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) was reduced 2-fold in the ABA group. In second-order neurons of the lateral hypothalamic area (LHA), melanin-concentrating hormone (MCH) mRNA expression was upregulated 2-fold in food-restricted running rats, but not in food-restricted sedentary controls. Prepro-orexin, CART and corticotropin-releasing hormone expression levels in the LHA and the paraventricular nucleus (PVN) were unchanged in both food-restricted groups. From this study it was concluded that during the development of ABA, neuropeptides in first-order neurons in the ARC and MCH in the LHA are regulated in an adequate response to negative energy balance, whereas expression levels of the other studied neuropeptides in secondary neurons of the LHA and PVN are unchanged and are probably regulated by factors other than energy status alone.

AMPA receptor blockade improves levodopa-induced dyskinesia in MPTP monkeys.

OBJECTIVE: To evaluate the contribution of amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) glutamate receptors to the pathogenesis of parkinsonian signs and levodopa-induced dyskinesias. BACKGROUND: Motor fluctuations and dyskinesias reflect, in part, altered function of glutamate receptors of the NMDA subtype. The possible role of AMPA receptors, however, has not yet been examined. METHODS: The authors compared the ability of an AMPA agonist (CX516) and a noncompetitive AMPA antagonist (LY300164) to alter parkinsonian symptoms and levodopa-induced dyskinesia in MPTP-lesioned monkeys. Eight levodopa-treated parkinsonian monkeys received rising doses of each drug, first in monotherapy and then in combination with low-, medium-, and high-dose levodopa. RESULTS: CX516 alone, as well as when combined with low-dose levodopa, did not affect motor activity but induced dyskinesia. Moreover, following injection of the higher doses of levodopa, it increased levodopa-induced dyskinesia by up to 52% (p < 0.05). LY300164 potentiated the motor activating effects of low-dose levodopa, increasing motor activity by as much as 86% (p < 0.05), and that of medium-dose levodopa as much as 54% (p < 0.05). At the same time, LY300164 decreased levodopa-induced dyskinesia by up to 40% (p < 0.05). CONCLUSIONS: AMPA receptor upregulation may contribute to the expression of levodopa-induced dyskinesia. Conceivably, noncompetitive AMPA receptor antagonists could be useful, alone or in combination with NMDA antagonists, in the treatment of PD, by enhancing the antiparkinsonian effects of levodopa without increasing and possibly even decreasing levodopa-induced dyskinesia.

Experiments with bar graph process supervision displays on VDUs.

Bar graph representations of process variables are compared with alternatives (stroke-type and 'T'-type, combined bar and stroke) in experiments with human subjects, using either an automatic slide projector or a closed-circuit TV system. The stroke-type appears to give superior results when used for detection of off-normal conditions.

Ten-fold enhancement of 2,4-D effect on water hyacinth by addition of gibberellic acid.

Under greenhouse conditions the effective concentration of 2,4-D (amine salt) for killing water hyacinths could be decreased 10 times if 2,k4-D was applied in combination with extremely low concentrations of gibberellic acid (6 g/ha or higher). This implies that in practice the risk of harming nearby vegetation is considerably reduced, and the cost of spraying programmes might be decreased.