Complex regional pain syndrome in a patient with neuroendocrine tumour under treatment with everolimus.

Everolimus is an immunosuppressant agent used in organ transplantation and, more recently, in cancer therapy. It has demonstrated beneficial effects in breast cancer, renal cancer, and neuroendocrine tumours. However, the treatment is not without side effects, some of which are still little known. We report the case of a 56 year-old man with a diagnosis of neuroendocrine tumour who developed a complex regional pain syndrome (CRPS) secondary to treatment with everolimus. CRPS has been linked to treatments with everolimus in renal and breast cancer patients as well as in renal transplant patients. To our knowledge, this is the first case of CRPS in a neuroendocrine tumour patient on everolimus treatment.

Tetraspanin1 promotes NGF signaling by controlling TrkA receptor proteostasis.

The molecular mechanisms that control the biosynthetic trafficking, surface delivery, and degradation of TrkA receptor are essential for proper nerve growth factor (NGF) function, and remain poorly understood. Here, we identify Tetraspanin1 (Tspan1) as a critical regulator of TrkA signaling and neuronal differentiation induced by NGF. Tspan1 is expressed by developing TrkA-positive dorsal root ganglion (DRG) neurons and its downregulation in sensory neurons inhibits NGF-mediated axonal growth. In addition, our data demonstrate that Tspan1 forms a molecular complex with the immature form of TrkA localized in the endoplasmic reticulum (ER). Finally, knockdown of Tspan1 reduces the surface levels of TrkA by promoting its preferential sorting towards the autophagy/lysosomal degradation pathway. Together, these data establish a novel homeostatic role of Tspan1, coordinating the biosynthetic trafficking and degradation of TrkA, regardless the presence of NGF.

Proteasome stress leads to APP axonal transport defects by promoting its amyloidogenic processing in lysosomes.

Alzheimer disease (AD) pathology includes the accumulation of poly-ubiquitylated (also known as poly-ubiquitinated) proteins and failures in proteasome-dependent degradation. Whereas the distribution of proteasomes and its role in synaptic function have been studied, whether proteasome activity regulates the axonal transport and metabolism of the amyloid precursor protein (APP), remains elusive. By using live imaging in primary hippocampal neurons, we showed that proteasome inhibition rapidly and severely impairs the axonal transport of APP. Fluorescence cross-correlation analyses and membrane internalization blockage experiments showed that plasma membrane APP does not contribute to transport defects. Moreover, by western blotting and double-color APP imaging, we demonstrated that proteasome inhibition precludes APP axonal transport by enhancing its endo-lysosomal delivery, where ß-cleavage is induced. Taken together, we found that proteasomes control the distal transport of APP and can re-distribute Golgi-derived vesicles to the endo-lysosomal pathway. This crosstalk between proteasomes and lysosomes regulates the intracellular APP dynamics, and defects in proteasome activity can be considered a contributing factor that leads to abnormal APP metabolism in AD.This article has an associated First Person interview with the first author of the paper.

The accuracy of estimating chronological age from Demirjian and Nolla methods in a Portuguese and Spanish sample.

BACKGROUND: Age determination has great importance in many clinical decisions, being commonly used in odontopediatrics, orthodontics, pediatrics, and forensic medicine. The Nolla and Demirjian et al. methods have been used for these purposes. However, estimating chronological age by means of the dental mineralization stage is not a straightforward analysis, and it is fundamental to test the validity of these methods and their applicability to populations. In this article we intend to compare the accuracy of estimating chronological age from dental age measured with the Nolla and Demirjian methods in a Portuguese and Spanish sample, considering the variables of sex and age-group. METHODS: The sample was composed of 821 orthopantomographs of healthy Portuguese (n = 270) and Spanish (n = 551) subjects from 4 to 34 years old. For the Nolla and Demirjian methods, seven mandibular left teeth were examined, staged according to the dental maturity scale of each method. We obtained a good index of inter-rater agreement, a good internal consistency for the teeth assessment, and a good temporal consistency. RESULTS: Dental age was calculated for each method. The Demirjian et al. method tends to overestimate the real age of participants and the Nolla method tends to underestimate it. The accuracy of both methods varied between the sexes and age groups. Both methods were found to be more precise with males. As the age-group increases, the predictive capacities of both methods diminish. The Nolla method was more accurate than the Demirjian method in early and late childhood for both sexes. Neither method could predict chronological age in adults. CONCLUSIONS: We can estimate chronological age for early and late childhood, through the Nolla and Demirjian methods, with the former showing greater predictive capacities than the latter. The Demirjian method tends to overestimate age and the Nolla method tends to underestimate it, leading to the importance of forming regression equations adapted to the population studied. Nolla and Demirjian formulas adapted to our sample were created as a function of sex and age-group.

Adapting Demirjian Standards for Portuguese and Spanish Children and Adolescents.

Estimation of children's chronological age is highly important in human and forensic sciences. The Demirjian method has been reported as accurate for this purpose. The literature review shows some evidence that the accuracy of estimating chronological age via the Demirjian standards is not a straightforward process. The objective of this research is to analyze the reliability of the Demirjian standards in Portuguese and Spanish children and adolescents and adapt it to include sex and group age as contingent factors. METHODS: Orthopantomographs of 574 Portuguese and Spanish male and female children and adolescents were employed to test the reliability of the Demirjian method. After testing for inter-rater consistency and age estimation using the Demirjian standards, multiple regression analysis was performed controlling for sex and age group. RESULTS: The Demirjian standards overestimated chronological age for both sexes, mainly for females. Through the development of regression functions, more detailed dental age estimation was performed. The predictive capacities of the Demirjian method and the significant teeth varied as a function of children's age. The Demirjian global standard predicted over 65% of the variance of the chronological age. Taking a tooth-by-tooth approach, the predictive ability increased by over 70%. CONCLUSIONS: The accuracy of estimating chronological age via the Demirjian method is not as reliable as it might appear, judging from the results found according to age group and according to sex crossed with age group.

Positive predictive value of ICD-9 codes 410 and 411 in the identification of cases of acute coronary syndromes in the Saskatchewan Hospital automated database.

BACKGROUND: Case definitions are essential to epidemiological research. OBJECTIVES: To evaluate ICD-9 codes 410 and 411 to identify cases of acute coronary syndromes (ACS), and the clinical information availability in the administrative and hospital discharge records of Saskatchewan, Canada. METHODS: In the context of a safety cohort study, we identified hospitalisations with primary discharge codes 410 (2260) and 411 (799). We selected all records with code 411, and a random sample (200) with code 410. Based on information obtained by trained abstractors from hospital records, events were classified by two cardiologists as definite or possible according to adapted AHA/ESC criteria. The validity of 410 and 411 codes was assessed by calculating the positive predictive value (PPV). Completeness of the recorded information on risk factors and use of aspirin was explored. RESULTS: The PPVs of the codes 410 and 411 for ACS were 0.96 (95%CI: 0. 92-0.98) and 0.86 (95%CI: 0.83-0.88), respectively. The PPV of 410 for acute myocardial infarction (AMI) was 0.95 (95%CI: 0.91-0.98). The PPV of 411 was 0.73 (95%CI: 0.70-0.77) for primary unstable angina (UA) and 0.09 (95%CI: 0.07-0.11) for AMI. Hospital charts review revealed key information for clinical variables, smoking, obesity and use of aspirin at admission. CONCLUSIONS: ICD-9 410 code has high PPV for AMI cases, likewise 411 for UA cases. Case validation remains important in epidemiological studies with administrative health databases. Given the pathophysiology of ACS, both AMI and UA might be used as study end points. In addition to code 410, we recommend the use of 411 plus validation.

αSynuclein control of mitochondrial homeostasis in human-derived neurons is disrupted by mutations associated with Parkinson's disease.

The etiology of Parkinson's disease (PD) converges on a common pathogenic pathway of mitochondrial defects in which α-Synuclein (αSyn) is thought to play a role. However, the mechanisms by which αSyn and its disease-associated allelic variants cause mitochondrial dysfunction remain unknown. Here, we analyzed mitochondrial axonal transport and morphology in human-derived neurons overexpressing wild-type (WT) αSyn or the mutated variants A30P or A53T, which are known to have differential lipid affinities. A53T αSyn was enriched in mitochondrial fractions, inducing significant mitochondrial transport defects and fragmentation, while milder defects were elicited by WT and A30P. We found that αSyn-mediated mitochondrial fragmentation was linked to expression levels in WT and A53T variants. Targeted delivery of WT and A53T αSyn to the outer mitochondrial membrane further increased fragmentation, whereas A30P did not. Genomic editing to disrupt the N-terminal domain of αSyn, which is important for membrane association, resulted in mitochondrial elongation without changes in fusion-fission protein levels, suggesting that αSyn plays a direct physiological role in mitochondrial size maintenance. Thus, we demonstrate that the association of αSyn with the mitochondria, which is modulated by protein mutation and dosage, influences mitochondrial transport and morphology, highlighting its relevance in a common pathway impaired in PD.

Role of neuronal activity and kinesin on tract tracing by manganese-enhanced MRI (MEMRI).

MEMRI offers the exciting possibility of tracing neuronal circuits in living animals by MRI. Here we use the power of mouse genetics and the simplicity of the visual system to test rigorously the parameters affecting Mn2+ uptake, transport and trans-synaptic tracing. By measuring electrical response to light before and after injection of Mn2+ into the eye, we determine the dose of Mn2+ with the least toxicity that can still be imaged by MR at 11.7 T. Using mice with genetic retinal blindness, we discover that electrical activity is not necessary for uptake and transport of Mn2+ in the optic nerve but is required for trans-synaptic transmission of this tracer to distal neurons in this pathway. Finally, using a kinesin light chain 1 knockout mouse, we find that conventional kinesin is a participant but not essential to neuronal transport of Mn2+ in the optic tract. This work provides a molecular and physiological framework for interpreting data acquired by MEMRI of circuitry in the brain.

Molecular magnetic properties of heteroporphyrins: a theoretical analysis.

B3LYP/6-31G(d) optimization of porphyrin, tetraphenylporphyrin and their 21,23-diheteroatom substituted derivatives with O, S, and Se heteroatoms was performed. A planar macrocycle was found in all cases except 21,23-dioxatetraphenylporphyrin which presents only slight deviations from planarity. A Bader analysis uncovers the presence of S-S and Se-Se interactions in the four corresponding heteroporphyrins, which appreciably distort the original unsubstituted macrocycles. In the minimum energy structures of heterotetraphenylporphyrins the four meso phenyl groups slant alternatively to right or left so that the two pairs of opposite phenyls present a staggered conformation. The pi current induced by a perpendicular magnetic field in porphyrin bifurcates across both types of pyrrole subunits but the presence of O, S and Se heteroatoms in 21,23-diheteroporphyrins causes a diminution of the current density through the inner section of the two heterorings and, consequently, the current path goes then through the outer section of these rings. The NICS values at the ring critical points of the heterorings are much larger (in absolute value) than those at the pyrrole ring critical points but appreciably smaller than that at the ring critical point of a pyrrole molecule. In agreement with experimental data the (1)H NMR present appreciable downfield shifts for the beta H atoms of the heterorings in the 21,23-heterosubstituted molecules.

Caries dental y su relación con la dieta cariogénica en pacientes atendidos por urgencias / Dental Caries and Its Association with Criogenic Diet in Patients Assisted at Emergency Service

Se realizó un estudio descriptivo de corte transversal, con el objetivo de determinar el comportamiento de la caries dental y su relación con la dieta cariogénica en pacientes de 15 y más años, que acudieron a la Consulta de Urgencia de la Clínica Mario Pozo Ochoa de diciembre de 2007 a noviembre de 2008, a los cuales se les realizó el examen bucal. Los datos se registraron en un formulario y los resultados se presentaron en tablas estadísticas...(AU)

A descriptive and cross- sectional study aimed at determining the behavior of dental caries and its association with cariogenic diet in patients of 15 years old and over was carried out. The patients were assissted at Emergency Service from Mario Pozo Dental Clinic from December 2007 to November 2008...(AU)

Formation of trichlorinated dibenzo-p-dioxins from 2,4-dichlorophenol and 2,4,5-trichlorophenolate: a theoretical study.

The reaction of the 2,4,5-trichlorophenolate anion with 2,4-dichlorophenol to afford trichlorinated dibenzo-p-dioxins (T3CDDs) is investigated at the B3LYP/6-31+G(d) and B3LYP/6-311+G(3df,2p)//B3LYP/6-31+G(d)+ZPVE(B3LYP/6-31+G(d)) levels of theory. The first stage of the process corresponds to the formation of a predioxin, which can evolve through four different routes. Two of them lead directly to the products 2,3,7-T3CDD and 1,3,8-T3CDD, and the other two afford different predioxin-type intermediates, which in turn can evolve through all or some of the four routes to give new predioxins or T3CDD. Consequently, the theoretical results obtained show plainly the complex chemistry implied in the formation of dioxins from chlorophenols via anionic mechanisms by disclosing all the critical structures through which the system evolves, thus allowing assessment of the viability of the different mechanistic routes and the accessible products. The statistical thermodynamics treatment at 1 atm and 298.15, 600, 900, and 1200 K indicates that at higher temperatures, the Gibbs energy barrier for the formation of the initial predioxin is clearly the rate-determining step for the whole process, but at lower temperatures the Gibbs energy barrier for this step is similar to those for its evolution into 2,3,7-T3CDD. This result is in contrast with previous proposals that the closure of the central ring is the rate-limiting step. Finally, according to our results the rate constant for the formation of polychlorinated dibenzo-p-dioxins increases with the temperature, in agreement with the experimental observation that the conversion of trichlorophenols increases when going from 600 to 900 K in the gas phase in the absence of catalysts, and with DFT molecular dynamics results.