Cortical activity evoked by inoculation needle prick in infants up to one-year old

Inoculation is one of the first and most common experiences of procedural pain in infancy. However, little is known about how needle puncture pain is processed by the central nervous system in children. In this study, we describe for the first time the event-related activity in the infant brain during routine inoculation using electroencephalography. Fifteen healthy term-born infants aged 1 to 2 months (n = 12) or 12 months (n = 5) were studied in an outpatient clinic. Pain behavior was scored using the Modified Behavioral Pain Scale. A distinct inoculation event-related vertex potential, consisting of 2 late negative-positive complexes, was observable in single trials after needle contact with the skin. The amplitude of both negative-positive components was significantly greater in the 12-month group. Both inoculation event-related potential amplitude and behavioral pain scores increased with age but the 2 measures were not correlated with each other. These components are the first recordings of brain activity in response to real-life needle pain in infants up to a year old. They provide new evidence of postnatal nociceptive processing and, combined with more traditional behavioral pain scores, offer a potentially more sensitive measure for testing the efficacy of analgesic protocols in this age group

Degeneration and regeneration of peripheral nerves: role of thrombin and its receptor PAR-1

The peripheral nervous system has a striking regeneration potential and after damage extensive changes in the differentiation state both of the injured neurons and of the Schwann cells are observed. Schwann cells, in particular, undergo a large scale change in gene expression becoming able to support axonal regeneration. Nerve injury is generally associated to inflammation and activation of the coagulation cascade. Thrombin acts as a polyfunctional signalling molecule exerting its physiological function through soluble target proteins and G-protein-coupled receptors, the protease-activated receptors (PARs) [1]. Recently, we have demonstrated that the activation of the main thrombin receptor, PAR-1, in Schwann cells favours their regenerative potential determining the release of factors which promote axonal regrowth [2]. The pro-regenerative potential of thrombin seems to be exerted in a narrow range of concentrations (pM-nM range). In fact, our preliminary data indicate that high levels of thrombin in the micromolar range slow down Schwann cell proliferation and induce cell death. On the contrary, PAR-1 activating peptides mimic the pro-survival but not the pro-apoptotic effects of thrombin. Controlling thrombin concentration may preserve neuronal health during nerve injury and represent a novel target for pharmacologic therapies

The Development of Nociceptive Network Activity in the Somatosensory Cortex of Freely Moving Rat Pups

Cortical perception of noxious stimulation is an essential component of pain experience but it is not known how cortical nociceptive activity emerges during brain development. Here we use continuous telemetric electrocorticogram (ECoG) recording from the primary somatosensory cortex (S1) of awake active rat pups to map functional nociceptive processing in the developing brain over the first 4 weeks of life. Cross-sectional and longitudinal recordings show that baseline S1 ECoG energy increases steadily with age, with a distinctive beta component replaced by a distinctive theta component in week 3. Event-related potentials were evoked by brief noxious hindpaw skin stimulation at all ages tested, confirming the presence of functional nociceptive spinothalamic inputs in S1. However, hindpaw incision, which increases pain sensitivity at all ages, did not increase S1 ECoG energy until week 3. A significant increase in gamma (20-50 Hz) energy occurred in the presence of skin incision at week 3 accompanied by a longer-lasting increase in theta (4-8 Hz) energy at week 4. Continuous ECoG recording demonstrates specific postnatal functional stages in the maturation of S1 cortical nociception. Somatosensory cortical coding of an ongoing pain "state" in awake rat pups becomes apparent between 2 and 4 weeks of age

Variability of the fimA gene in Porphyromonas gingivalis isolated from periodontitis and non-periodontitis patients

Objective: The goal of this study was to determine the genetic variability of the fimA gene in Porphyromonas gingivalis isolates from Spanish patients. Study Design: Pooled subgingival samples were taken, processed and cultured in non-selective blood agar medium. Pure cultures of one to six isolates per patient were obtained and PCR and PCR-RFLP were used for fimbrillin gene (fimA) type determination of the extracted genomic (DNA). Results: Two hundred and twenty four Porphyromonas gingivalis isolates from 65 patients were analyzed consisting of 15 non-periodontitis patients (66 isolates) and 50 with periodontitis (158 isolates). Genotype II was the most prevalent (50.9%), while the other types of fimbriae did not exceed fifteen percent of prevalence. Isolates with types II and IV of fimbriae were significantly more prevalent in periodontitis patients than isolates with genotype I. Co-infection was observed in 17.65% of the patients analyzed. Conclusion: The results suggest that in this population Porphyromonas gingivalis with type II of fimbriae are significantly more predominant in periodontitis patients than genotype I

Impairment of the autophagic flux in astrocytes intoxicated by trimethyltin

Autophagy is a lysosomal catabolic route for protein aggregates and damaged organelles which in different stress conditions, such as starvation, generally improves cell survival. An impairment of this degradation pathway has been reported to occur in many neurodegenerative processes. Trimethyltin (TMT) is a potent neurotoxin present as an environmental contaminant causing tremors, seizures and learning impairment in intoxicated subjects. The present data show that in rat primary astrocytes autophagic vesicles (AVs) appeared after few hours of TMT treatment. The analysis of the autophagic flux in TMT-treated astrocytes was consistent with a block of the late stages of autophagy and was accompanied by a progressive accumulation of the microtubule associated protein light chain 3 (LC3) and of p62/SQSTM1. Interestingly, an increased immunoreactivity for p62/SQSTM1 was also observed in hippocampal astrocytes detected in brain slices of TMT-intoxicated rats. The time-lapse recordings of AVs in EGFP-mCherry-LC3B transfected astrocytes demonstrated a reduced mobility of autophagosomes after TMT exposure respect to control cells. The observed block of the autophagic flux cannot be overcome by known autophagy inducers such as rapamycin or 0.5mM lithium. Although ineffective when used at 0.5mM, lithium at higher concentrations (2mM) was able to protect astrocyte cultures from TMT toxicity. This effect correlated well with its ability to determine the phosphorylation/inactivation of glycogen kinase synthase-3β (GSK-3β)

Encoding of mechanical nociception differs in the adult and infant brain

Newborn human infants display robust pain behaviour and specific cortical activity following noxious skin stimulation, but it is not known whether brain processing of nociceptive information differs in infants and adults. Imaging studies have emphasised the overlap between infant and adult brain connectome architecture, but electrophysiological analysis of infant brain nociceptive networks can provide further understanding of the functional postnatal development of pain perception. Here we hypothesise that the human infant brain encodes noxious information with different neuronal patterns compared to adults. To test this we compared EEG responses to the same time-locked noxious skin lance in infants aged 0-19 days (n = 18, clinically required) and adults aged 23-48 years (n = 21). Time-frequency analysis revealed that while some features of adult nociceptive network activity are present in infants at longer latencies, including beta-gamma oscillations, infants display a distinct, long latency, noxious evoked 18-fold energy increase in the fast delta band (2-4 Hz) that is absent in adults. The differences in activity between infants and adults have a widespread topographic distribution across the brain. These data support our hypothesis and indicate important postnatal changes in the encoding of mechanical pain in the human brain

BMJ Open

ObjectivesThe raising unit price of cigarette has been shown to be one of the most effective ways of reducing cigarette consumption and increasing rates of successful quitting. However, researchers have shown that price-sensitive smokers have used a variety of strategies to mitigate the effect of the rising price of cigarettes on their smoking habits. In particular, 23\ue2\u20ac\u201c34% of adult smokers in the US use cheaper brands, and 18\ue2\u20ac\u201c55% use coupons or promotions. Little is known about the discount use by type of brands. As such, the main purpose of this analysis is to evaluate the uses and price discount effects of these price-related discounts by manufacturers and major brands.SettingAn analysis based on the cross-sectional 2009\ue2\u20ac\u201c2010 National Adult Tobacco Survey (NATS).Participants11\ue2\u20ac\u2026766 current smokers aged 18 or above in the USA.Primary outcome measuresPrice-related discount was defined as smokers who used coupons, rebates, buy-one-get-one-free, two-for-one or any other special promotions for their last cigarettes purchase.ResultsThe use of price-related discounts and associated price impact vary widely by cigarette manufacturer and brand. Approximately one of three Camel, one of four Marlboro and one of eight Newport smokers used price-related discounts on their latest cigarette purchases. The average price reductions of discounts offered by Philip Morris (PM) or R.J. Reynolds (RJR) were around 29 cents per pack while that of Lorillard (Newport only) was 24 cents per pack. Cigarette brands that provided significant per pack price reductions include: PM Marlboro (28 cents), RJR brand Camel (41 cents), Doral (50 cents), Kool (73 cents) and Salem (80 cents), and Lorillard Newport (24 cents).ConclusionsPolicies that decrease price-minimisation strategies will benefit public health

Increased tumor necrosis factor alpha-converting enzyme activity induces insulin resistance and hepatosteatosis in mice

Tumor necrosis factor alpha-converting enzyme (TACE, also known as ADAM17) was recently involved in the pathogenesis of insulin resistance. We observed that TACE activity was significantly higher in livers of mice fed a high-fat diet (HFD) for 1 month, and this activity was increased in liver > white adipose tissue > muscle after 5 months compared with chow control. In mouse hepatocytes, C(2)C(12) myocytes, and 3T3F442A adipocytes, TACE activity was triggered by palmitic acid, lipolysaccharide, high glucose, and high insulin. TACE overexpression significantly impaired insulin-dependent phosphorylation of AKT, GSK3, and FoxO1 in mouse hepatocytes. To test the role of TACE activation in vivo, we used tissue inhibitor of metalloproteinase 3 (Timp3) null mice, because Timp3 is the specific inhibitor of TACE and Timp3(-/-) mice have higher TACE activity compared with wild-type (WT) mice. Timp3(-/-) mice fed a HFD for 5 months are glucose-intolerant and insulin-resistant; they showed macrovesicular steatosis and ballooning degeneration compared with WT mice, which presented only microvesicular steatosis. Shotgun proteomics analysis revealed that Timp3(-/-) liver showed a significant differential expression of 38 proteins, including lower levels of adenosine kinase, methionine adenosysltransferase I/III, and glycine N-methyltransferase and higher levels of liver fatty acid-binding protein 1. These changes in protein levels were also observed in hepatocytes infected with adenovirus encoding TACE. All these proteins play a role in fatty acid uptake, triglyceride synthesis, and methionine metabolism, providing a molecular explanation for the increased hepatosteatosis observed in Timp3(-/-) compared with WT mice. Conclusion: We have identified novel mechanisms, governed by the TACE-Timp3 interaction, involved in the determination of insulin resistance and liver steatosis during overfeeding in mice

Extended Beta models for poverty mapping. An application integrating survey and remote sensing data in Bangladesh

The paper targets the estimation of a poverty rate at the upazila level in Bangladesh through the use of demographic and health survey (DHS) data. Upazilas are administrative regions equivalent to counties or boroughs whose sample sizes are not large enough to provide reliable estimates or are even absent. We tackle this issue by proposing a small-area estimation model complementing survey data with remote sensing information at the area level. We specify an extended Beta mixed regression model within the Bayesian framework, allowing it to accommodate the peculiarities of sample data and to predict out-of-sample rates. Specifically, it enables to include estimates equal to either 0 or 1 and to model the strong intra-cluster correlation. We aim at proposing a method that can be implemented by statistical offices as a routine. In this spirit we consider a regularizing prior for coefficients, rather than a model selection approach, to deal with a large number of auxiliary variables. We compare our methods with existing alternatives using a design-based simulation exercise and illustrate its potential with the motivating application

A Mixture-of-Experts model to deal with the rural/urban dichotomy in small area estimation

Small area estimation is a pivotal statistical methodology for generating reliable estimates of socio-economic indicators across small sub-populations. This research focuses on estimating the per capita wealth index in Bangladeshi upazilas, by integrating data from the Demographic and Health Survey with remote sensing covariates. The Fay–Herriot model, a prominent area-level model in small area literature, shows limitations when applied to our data. Notably, an exploratory analysis unveils two distinct regimes in the data generating process, characterized by the rural/urban dichotomy. To tackle this issue, we extend the Fay–Herriot model through a Mixture-of-Experts, which classifies areas into groups within the estimation process. This enhances flexibility while preserving desirable properties, such as design consistency and interpretability of predictors. In addition, this family of models defines the mixing probabilities through a logistic regression, which proved to be particularly efficient in our applied setting, as demonstrated by a simulation study