Neurophysiology and genetics of burning mouth syndrome

Background and aims: Neuropathic mechanisms are involved in burning mouth syndrome (BMS), and variation of the dopamine D2 receptor (DRD2) gene contributes to experimental pain perception. We investigated whether neurophysiologic findings differ in BMS patients compared to healthy controls, and whether 957C>T polymorphism of the DRD2 gene influences thermal sensitivity or pain experience in BMS.Methods: Forty‐five BMS patients (43 women), mean age 62.5 years, and 32 healthy controls (30 women), mean age 64.8 years, participated. Patients estimated pain intensity, interference, suffering and sleep with Numeric Rating Scale. Blink reflex tests of the supraorbital (SON), mental (MN) and lingual (LN) nerves, and thermal quantitative sensory testing were done. The results were analysed with ANOVA. DRD2 gene 957C>T polymorphism was determined in 31 patients, and its effects on neurophysiologic and clinical variables were analysed.Results: Cool (p = 0.0090) and warm detection thresholds (p = 0.0229) of the tongue were higher in BMS patients than controls. The stimulation threshold for SON BR was higher in patients than in controls (p = 0.0056). The latencies of R2 component were longer in BMS patients than in controls (p = 0.0005) at the SON distribution. Habituation of SON BR did not differ between the groups. The heat pain thresholds were highest (p = 0.0312) in homozygous patients with 957TT, who also reported most interference (p = 0.0352) and greatest suffering (p = 0.0341). Genotype 957CC associated with sleep disturbances (p = 0.0254).Conclusions: Burning mouth syndrome patients showed thermal hypoesthesia within LN distribution compatible with small fibre neuropathy. The DRD2 957C>T genotype influences perception and experience of BMS pain.Significance: The results confirm earlier findings of neuropathic pain in BMS. The DRD2 957 C>T genotype influences perception and experience of clinical pain in BMS.</p

Risk factors for acute respiratory tract infections in general practitioner patients in The Netherlands: a case-control study

<p>Abstract</p> <p>Background</p> <p>Acute respiratory tract infections (ARTI) are an important public health problem. Improved identification of risk factors might enable targeted intervention. Therefore we carried out a case-control study with the aim of identifying environmental risk factors for ARTI consultations in the Dutch general population.</p> <p>Methods</p> <p>A subset of patients visiting their GP in the period of 2000–2003 with an ARTI (cases) and age-matched controls (visiting for other complaints) were included in a case-control study. They were asked to complete a questionnaire about potential risk factors. Conditional logistic regression was used to calculate odds ratio's (OR) and 95% confidence intervals (CI) to estimate the independent effect of potential risk factors.</p> <p>Results</p> <p>A total of 493 matched pairs of case and control subjects were enrolled. Exposure to persons with respiratory complaints, both inside and outside the household, was found to be an independent risk factor for visiting a GP with an ARTI (respectively OR_adj= 1.9 and OR_adj= 3.7). Participants exposed to dampness or mould at home (OR_adj=0.5) were significantly less likely to visit their GP. In accordance with the general risk of consultations for ARTI, participants with a laboratory-confirmed ARTI who were exposed to persons with respiratory complaints outside the household were also significantly more likely to visit their GP (OR_adj=2.5).</p> <p>Conclusion</p> <p>This study confirmed that heterogeneity in the general population as well as in pathogens causing ARTI makes it complicated to detect associations between potential risk factors and respiratory infections. Whereas it may be difficult to intervene on the risk posed by exposure to persons with respiratory complaints, transmission of ARTI in the general population might be reduced by improved hygienic conditions.</p

Tumor Associated Macrophages Protect Colon Cancer Cells from TRAIL-Induced Apoptosis through IL-1β- Dependent Stabilization of Snail in Tumor Cells

We recently reported that colon tumor cells stimulate macrophages to release IL-1beta, which in turn inactivates GSK3beta and enhances Wnt signaling in colon cancer cells, generating a self-amplifying loop that promotes the growth of tumor cells.Here we describe that macrophages protect HCT116 and Hke-3 colon cancer cells from TRAIL-induced apoptosis. Inactivation of IL-1beta by neutralizing IL-1beta antibody, or silencing of IL-1beta in macrophages inhibited their ability to counter TRAIL-induced apoptosis. Accordingly, IL-1beta was sufficient to inhibit TRAIL-induced apoptosis. TRAIL-induced collapse of the mitochondrial membrane potential (Delta psi) and activation of caspases were prevented by macrophages or by recombinant IL-1beta. Pharmacological inhibition of IL-1beta release from macrophages by vitamin D(3), a potent chemopreventive agent for colorectal cancer, restored the ability of TRAIL to induce apoptosis of tumor cells cultured with macrophages. Macrophages and IL-1beta failed to inhibit TRAIL-induced apoptosis in HCT116 cells expressing dnIkappaB, dnAKT or dnTCF4, confirming that they oppose TRAIL-induced cell death through induction of Wnt signaling in tumor cells. We showed that macrophages and IL-1beta stabilized Snail in tumor cells in an NF-kappaB/Wnt dependent manner and that Snail deficient tumor cells were not protected from TRAIL-induced apoptosis by macrophages or by IL-1beta, demonstrating a crucial role of Snail in the resistance of tumor cells to TRAIL.We have identified a positive feedback loop between tumor cells and macrophages that propagates the growth and promotes the survival of colon cancer cells: tumor cells stimulate macrophages to secrete IL-1beta, which in turn, promotes Wnt signaling and stabilizes Snail in tumor cells, conferring resistance to TRAIL. Vitamin D(3) halts this amplifying loop by interfering with the release of IL-1beta from macrophages. Accordingly, vitamin D(3) sensitizes tumor cells to TRAIL-induced apoptosis, suggesting that the therapeutic efficacy of TRAIL could be augmented by this readily available chemopreventive agent

Weaning practices in phenylketonuria vary between health professionals in Europe

Background: In phenylketonuria (PKU), weaning is considered more challenging when compared to feeding healthy infants. The primary aim of weaning is to gradually replace natural protein from breast milk or standard infant formula with solids containing equivalent phenylalanine (Phe). In addition, a Phe-free second stage L-amino acid supplement is usually recommended from around 6 months to replace Phe-free infant formula. Our aim was to assess different weaning approaches used by health professionals across Europe. Methods: A cross sectional questionnaire (survey monkey (R)) composed of 31 multiple and single choice questions was sent to European colleagues caring for inherited metabolic disorders (IMD). Centres were grouped into geographical regions for analysis. Results: Weaning started at 17-26 weeks in 85% (n=81/95) of centres, > 26 weeks in 12% (n=11/95) and 26 weeks. First solids were mainly low Phe vegetables (59%, n=56/95) and fruit (34%, n=32/95). A Phe exchange system to allocate dietary Phe was used by 52% (n=49/95) of centres predominantly from Northern and Southern Europe and 48% (n=46/95) calculated most Phe containing food sources (all centres in Eastern Europe and the majority from Germany and Austria). Some centres used a combination of both methods. A second stage Phe-free L-amino acid supplement containing a higher protein equivalent was introduced by 41% (n=39/95) of centres at infant age 26-36 weeks (mainly from Germany, Austria, Northern and Eastern Europe) and 37% (n=35/95) at infant age > 1y mainly from Southern Europe. 53% (n=50/95) of centres recommended a second stage Phe-free L-amino acid supplement in a spoonable or semi-solid form. Conclusions: Weaning strategies vary throughout European PKU centres. There is evidence to suggest that different infant weaning strategies may influence longer term adherence to the PKU diet or acceptance of Phe-free L-amino acid supplements; rendering prospective long-term studies important. It is essential to identify an effective weaning strategy that reduces caregiver burden but is associated with acceptable dietary adherence and optimal infant feeding development.Peer reviewe

Early feeding practices in infants with phenylketonuria across Europe

Background: In infants with phenylketonuria (PKU), dietary management is based on lowering and titrating phenylalanine (Phe) intake from breast milk or standard infant formula in combination with a Phe-free infant formula in order to maintain blood Phe levels within target range. Professionals use different methods to feed infants with PKU and our survey aimed to document practices across Europe. Methods: We sent a cross sectional, survey monkey (R) questionnaire to European health professionals working in IMD. It contained 31 open and multiple-choice questions. The results were analysed according to different geographical regions. Results: Ninety-five centres from 21 countries responded. Over 60% of centres commenced diet in infants by age 10 days, with 58% of centres implementing newborn screening by day 3 post birth. At diagnosis, infant hospital admission occurred in 61% of metabolic centres, mainly in Eastern, Western and Southern Europe. Breastfeeding fell sharply following diagnosis with only 30% of women still breast feeding at 6 months. 53% of centres gave pre-measured Phe-free infant formula before each breast feed and 23% alternated breast feeds with Phe-free infant formula. With standard infant formula feeds, measured amounts were followed by Phe-free infant formula to satiety in 37% of centres (n = 35/95), whereas 44% (n = 42/95) advised mixing both formulas together. Weaning commenced between 17 and 26 weeks in 85% centres, >= 26 weeks in 12% and <17 weeks in 3%. Discussion: This is the largest European survey completed on PKU infant feeding practices. It is evident that practices varied widely across Europe, and the practicalities of infant feeding in PKU received little focus in the PKU European Guidelines (2017). There are few reports comparing different feeding techniques with blood Phe control, Phe fluctuations and growth. Controlled prospective studies are necessary to assess how different infant feeding practices may influence longer term feeding development.Peer reviewe

Combining Semi-Physical and Neural Network Modeling: An Example of Its Usefulness

. We illustrate the power of combining semi-physical and neural network modeling in an application example. It is argued that some of the problems related to the use of neural networks, such as high dimensionality of the parameter space and problems with local minima, can be alleviated using this approach. Key Words. Nonlinear system identification; semi-physical modeling; neural network modeling. 1. INTRODUCTION System identification as described by, e.g., Ljung (1987) is a well established methodology for designing mathematical models of dynamical systems using input-output data. After experiment design, the problem can be split into two parts: model structure selection followed by parameter estimation. While various least-squares type of algorithms are predominant for parameter estimation, one has a large spectrum of model structure approaches to choose between. Physically parameterized modeling (where all physical insight about the system is condensed into the model) is a quite t..

Combining Semi-Physical and Neural Network Modeling: An Example of Its Usefulness

: This paper illustrates the power of combining semi-physical and neural network modeling in an application example. It is argued that some of the problems related to the use of neural networks, such as high dimensionality of the parameter space and problems with undesired local minima, can be alleviated by this approach. Keywords: Nonlinear system identification; semi-physical modeling; neural nets. 1. INTRODUCTION System identification as it is described by, e.g., (Ljung, 1987) is a well established methodology for designing mathematical models of dynamical systems using input-output data. After experiment design, the problem can be split into two different parts: model structure selection followed by parameter estimation. While various least-squares type of algorithms are predominant for parameter estimation, one has a large spectrum of model structures to choose between. Physically parameterized modeling (where all the physical insight about the system is condensed into the model)..