Comparison of analgesic effects of single versus repeated injection of botulinum toxin in orofacial formalin test in rats

Long-term effectiveness and repeated administration of botulinum toxin A are the basis for its use in both neuromuscular disorders and certain painful conditions. Botulinum toxin A has been recently approved for migraine treatment, and its off-label use extends to other craniofacial pain disorders. However, recently it was reported that, after repeated injection, botulinum toxin loses its antinociceptive efficacy in rats. In present study with a similar design, we compared the effects of single and repeated injections of botulinum toxin in formalin-induced orofacial pain. No statistically significant differences were found between single or repeatedly treated animal groups. Our results are in line with the clinical experience and suggest that botulinum toxin can be re-administered in orofacial pain treatment.     

Admixed phenotype of NEDD4L associated periventricular nodular heterotopia: A case report

Rationale:Periventricular nodular heterotopia-7 (PVNH7) is a neurodevelopmental disorder associated with improper neuronal migration during neurogenesis in cortex development caused by pathogenic variants in the NEDD4L gene.Patient concerns:We report the case of a polystigmatized 2-year-old boy having significant symptomatologic overlap with PVNH7, such as delayed psychomotor and mental development, seizures and infantile spasms, periventricular nodular heterotopia, polymicrogyria, cleft palate, 2 to 3 toe syndactyly, hypotonia, microretrognathia, strabismus, and absent speech and walking. The patient showed also distinct symptoms falling outside PVNH7 symptomatology, also present in the proband''s older brother, such as blue sclerae, hydronephrosis, transversal palmar crease (found also in their father), and bilateral talipes equinovarus. In addition, the patient suffered from many other symptoms.Diagnoses:The boy, his brother and their parents were subjected to whole-exome sequencing. Because of uncertainties in symptomatology and inheritance pattern, the top-down approach was hard to apply. Using the bottom-up approach, we identified a known pathogenic variant, NM_001144967.2(NEDD4L):c.2677G>A:p.Glu893Lys, in the proband''s genome that absented in any other analyzed family member, suggesting its de novo origin.Interventions and outcomes:The patient was treated with Convulex 300 mg/mL for the successful seizure control and Euthyrox 25mg for the treatment of thyroid malfunction. He also took various supplements for the metabolism support and digestion regulation. Moreover, the patient underwent the corrective surgeries of cleft palate and talipes equinovarus.Lessons:We successfully identified the causative mutation NM_001144967.2(NEDD4L):c.2677G>A:p.Glu893Lys explaining symptoms overlapping those reported for PVNH7. Symptoms shared with the brother were not explained by this variant, since he was not a carrier of the pathogenic NEDD4L variant. These are most likely not extended phenotypes of PVNH7, rather an independent clinical entity caused by a yet unidentified genetic factor in the family, highlighting thus the importance of thorough evaluation of symptomatology and genomic findings in affected and unaffected family members, when such data are available.     

Transient structural MRI patterns correlate with the motor functions in preterm infants

AimTo explore the relationships between transient structural brain patterns on MRI at preterm and at term-equivalent age (TEA) as a predictor of general movements (GMs) and motor development at 1-year corrected age (CA) in very preterm infants.MethodsIn this prospective study, 30 very preterm infants (median = 28wks; 16 males) had structural magnetic resonance imaging (MRI) at preterm (median = 31wks + 6d) and at TEA (median = 40wks) and neuromotor assessments. The quality of GMs was assessed by Prechtl’s general movements assessment and a detailed analysis of the motor repertoire was performed by calculating a motor optimality score (MOS), both at term age and at 3 months post-term. Motor development at 1-year CA was evaluated with the Infant Motor Profile (IMP). Associations between qualitative MRI findings and neuromotor scores were investigated.ResultsAbnormal GMs and low motor performance at 1-year CA were associated with the poor visibility of transient structural pattern, that is with sagittal strata.InterpretationTransient structural MRI pattern, sagittal strata, at preterm age is related to the quality of GMs and later motor development in preterm infants. This transient fetal brain compartment may be considered as a component of neurobiological basis for early neuromotor behavior, as expressed by GMs.     

Shear stress-induced up-regulation of the intermediate-conductance Ca(2+)-activated K(+) channel in human endothelium

OBJECTIVE: Wall shear stress associated with blood flow is a major stimuli for generation of endothelial vasodilating and antithrombotic factors and it also regulates endothelial gene expression. Activation of endothelial intermediate-conductance Ca(2+)-activated K(+) channels (IK(Ca)) is important for the control of endothelial function by inducing cell hyperpolarization and thus generation of the endothelium-derived hyperpolarizing factor. In the present study we tested whether the IK(Ca) encoding IKCa1 gene is regulated by laminar shear stress (LSS). METHODS: Human umbilical vein endothelial cells (HUVEC) were subjected to LSS with a magnitude of 0.5-15 dyn/cm(2) and time intervals of 2-24 h in a flow cone apparatus. Expression of the IKCa1 gene and IK(Ca)-functions were determined by using real time RT-PCR and patch-clamp techniques. RESULTS: A short 2-4 h-or long 24 h-exposure to a LSS with a low (venous) magnitude of 0.5 dyn/cm(2) had no effect on IKCa1 expression levels. An exposure for 2 and 4 h to LSS with an intermediate magnitude of 5 dyn/cm(2) was also ineffective, whereas an exposure for 24 h induced a significant threefold up-regulation of IKCa1 expression levels. An exposure to LSS with a higher (arterial) magnitude of 15 dyn/cm(2), resulted in an eightfold up-regulation of IKCa1 expression levels after a 4 h-exposure and a fourfold increase of IKCa1 expression levels at 24 h. The increased IKCa1 expression levels following exposure to high levels of LSS resulted in enhanced IK(Ca) whole-cell currents and in an increased hyperpolarization of the endothelium in response to ATP and the IK(Ca) opener 1-EBIO. Inhibition of the mitogen-activated protein kinase/extracellular-signal-regulated kinase (ERK) kinase 1/2 (MEK/ERK) pathway by PD98059 prevented the LSS-induced up-regulation of IKCa1 expression levels and IK(Ca) whole-cell currents indicating that augmentation of IKCa1 expression levels is mediated by the LSS-induced activation of the MEK/ERK pathway. CONCLUSION: Long term exposure to LSS up-regulates expression and function of endothelial IK(Ca). This increase might represent a new important mechanism in endothelial adaptation to altered hemodynamics.     

Assessment of Hemodialysis Adequacy by Ionic Dialysance: Comparison to Standard Method of Urea Removal

Background. The hemodialysis adequacy is one of the most important issues influencing the survival of patients on maintenance hemodialysis (HD). Assessment of measuring the delivered dialysis dose using clearance × time/volume (Kt/V) index requires multiple blood sampling. New methods for assessment of dialysis dose based on ionic dialysance (ID) have been suggested. Online conductivity monitoring (using sodium flux as a surrogate for urea) allows the repeated noninvasive measurement of Kt/V on each HD treatment. In this study we have compared this method with the standard method of estimating Kt/V. Methods. We studied 24 established HD patients over a 4 week time period. Patients were dialyzed using Fresenius 4008S dialysis monitors, equipped with modules to measure ID. Data were manually collected and analyzed using the appropriate statistical software. Urea removal (UR) was measured once a week by a two-pool calculation, estimating an eKt/V. Results. The Kt/V measured by ID highly correlated with the one derived from the measurement of the UR (r = 0.8959, p< 0.0001). The ID underestimated UR by the mean of 6%. The ID varied greatly within individual patients with a median of 1.29 ± 0.22. If the eKt/V ≥ 1.2 is considered adequate, 33% of the patients would have been inadequately dialyzed. The mean HD duration to achieve an adequate dialysis was 4 hours and 47 minutes with high interpatient variability. Conclusion. The ID seems to be an easily obtained measure of the delivered dialysis dose, correlating well with standard UR method. Substantial individual variations imply that repeated measures (ideally for all treatments) are necessary to obtain a real answer to the mean treatment dose being delivered to the patients.     

Social participation in early and established rheumatoid arthritis patients

Purpose: The aim of the study was to examine whether rheumatoid arthritis (RA) patients with different levels of restriction in social participation differ in disease related as well as psychosocial variables and whether a similar pattern can be found among early and established RA patients.

Method: Two samples of RA patients with early (n?=?97; age?=?53?±?12.3 years; disease duration?= 2.8?±?1.2 years; 76% women) and established (n?=?143; age?=?58?±?10.3 years; disease duration?= 16.1?±?3.6 years; 86% women) were collected. The pattern of differences for the patients with different level of participation restriction (no restriction, mild, moderate or high restriction) was explored by the Jonckheere–Terpstra test. Results: Significant differences were found between patients with different levels of social participation restrictions in both samples in pain, fatigue, functional disability, anxiety, depression and mastery. Generally, it was found that patients with higher restrictions experienced more pain and fatigue, more anxiety and depression and reported lower mastery. Similar pattern of differences concerning disease activity and self-esteem was found mainly in the established group. Conclusions: The study shows that the level of perceived restrictions in social participation are highly relevant regarding the disease related variables such as pain, fatigue and functional disability as well as psychological status and personal resources in both early and established RA.

• Implications for Rehabilitation

• Supporting involvement and participation of individuals with rheumatoid arthritis is important for decreasing the impact of RA symptoms on everyday life.

• Recognition and empowerment of individual resources such a mastery and self-esteem of RA patients could be beneficial for overcoming restrictions in participation.

     

Role of positron emission tomography and bone scintigraphy in the evaluation of bone involvement in metastatic pheochromocytoma and paraganglioma: specific implications for succinate dehydrogenase enzyme subunit B gene mutations

We performed a retrospective analysis of 71 subjects with metastatic pheochromocytoma and paraganglioma (30 subjects with mutation of succinate dehydrogenase enzyme subunit B (SDHB) gene and 41 subjects without SDHB mutation). Sixty-nine percent presented with bone metastases (SDHB +/-: 77% vs 63%), 39% with liver metastases (SDHB +/-: 27% vs 47%), and 32% with lung metastases (SDHB +/-: 37% vs 29%). The most common sites of bone involvement were thoracic spine (80%; SDHB+/-: 83% vs 77%), lumbar spine (78%; SDHB +/-: 78% vs 75%), and pelvic and sacral bones (78%; SDHB +/-: 91% vs 65%, P=0.04). Subjects with SDHB mutation also showed significantly higher involvement of long bones (SDHB +/-: 78% vs 30%, P=0.007) than those without the mutation. The best overall sensitivity in detecting bone metastases demonstrated positron emission tomography (PET) with 6-[(18)F]-fluorodopamine ([(18)F]-FDA; 90%), followed by bone scintigraphy (82%), computed tomography or magnetic resonance imaging (CT/MRI; 78%), 2-[(18)F]-fluoro-2-deoxy-d-glucose ([(18)F]-FDG) PET (76%), and scintigraphy with [(123/131)I]-metaiodobenzylguanidine (71%). In subjects with SDHB mutation, imaging modalities with best sensitivities for detecting bone metastases were CT/MRI (96%), bone scintigraphy (95%), and [(18)F]-FDG PET (92%). In subjects without SDHB mutations, the modality with the best sensitivity for bone metastases was [(18)F]-FDA PET (100%). In conclusion, bone scintigraphy should be used in the staging of patients with malignant pheochromocytoma and paraganglioma, particularly in patients with SDHB mutations. As for PET imaging, [(18)F]-FDG PET is highly recommended in SDHB mutation patients, whereas [(18)F]-FDA PET is recommended in patients without the mutation.