Quantitative and qualitative assessment of plasma cell dyscrasias in dual-layer spectral CT.

OBJECTIVES: Virtual non-calcium (VNCa) images could improve assessment of plasma cell dyscrasias by enhancing visibility of bone marrow. Thus, VNCa images from dual-layer spectral CT (DLCT) were evaluated at different calcium suppression (CaSupp) indices, correlating results with apparent diffusion coefficient (ADC) values from MRI. METHODS: Thirty-two patients with initial clinical diagnosis of a plasma cell dyscrasia before any chemotherapeutic treatment, who had undergone whole-body low-dose DLCT and MRI within 2 months, were retrospectively enrolled. VNCa images with CaSupp indices ranging from 25 to 95 in steps of 10, conventional CT images, and ADC maps were quantitatively analyzed using region-of-interests in the vertebral bodies C7, T12, L1-L5, and the iliac bone. Independent two-sample t-test, Wilcoxon-signed-rank test, Pearson's correlation, and ROC analysis were performed. RESULTS: Eighteen patients had a non-diffuse, 14 a diffuse infiltration in conventional MRI. A significant difference between diffuse and non-diffuse infiltration was shown for VNCa-CT with CaSupp indices from 55 to 95, for conventional CT, and for ADC (each p < 0.0001). Significant quantitative correlation between VNCa-CT and MRI could be found with strongest correlation at CaSupp index 65 for L3 (r = 0.68, p < 0.0001) and averaged L1-L5 (r = 0.66, p < 0.0001). The optimum CT number cut-off point for differentiation between diffuse and non-diffuse infiltration at CaSupp index 65 for averaged L1-L5 was -1.6 HU (sensitivity 78.6%, specificity 75.0%). CONCLUSION: Measurements in VNCa-CT showed the highest correlation with ADC at CaSupp index 65. VNCa technique may prove useful for evaluation of bone marrow infiltration if MRI is not feasible. KEY POINTS: • VNCa-CT images can support the evaluation of bone marrow infiltration in plasma cell dyscrasias. • VNCa measurements of vertebral bodies show significant correlation with ADC in MRI. • Averaging L1-L5 at CaSupp index 65 allowed quantitative detection of infiltration comparable to MRI ADC.

Pedestrian hit by a car impacted metal pole: reconstructing the head load.

Fatal head injuries are frequently seen in pedestrians hit by motorized vehicles. In our case, the pedestrian sustained a devastating head injury with skull splitting in the mediosagittal plane. A car collided with a traffic sign causing a bending of the pole. The metal pole hit a man standing close beside it; the man had a head injury severity that is more commonly due to falling objects than due to traffic accidents. Assuming a head mass of 5 kg, simplified calculations yield maximum contact forces of ca. 36 kN exceeding mean parietal fracture forces which are in the order of magnitude of 12.5 kN. The influences of the effective body mass and the horizontal distance between the pole and the pedestrian on maximum contact forces are investigated. High contact forces in our case can be mainly explained by the comparably high impact velocity and by a partial mass transfer of the total car mass to the pole.

Reliability and main findings of the flexible endoscopic evaluation of swallowing-Tensilon test in patients with myasthenia gravis and dysphagia.

BACKGROUND AND PURPOSE: Diagnosis of pharyngeal dysphagia caused by myasthenia gravis (MG) based on clinical examination alone is often challenging. Flexible endoscopic evaluation of swallowing (FEES) combined with Tensilon (edrophonium) application, referred to as the FEES-Tensilon test, was developed to improve diagnostic accuracy and to detect the main symptoms of pharyngeal dysphagia in MG. Here we investigated inter- and intra-rater reliability of the FEES-Tensilon test and analyzed the main endoscopic findings. METHODS: Four experienced raters reviewed a total of 20 FEES-Tensilon test videos in randomized order. Residue severity was graded at four different pharyngeal spaces before and after Tensilon administration. All interpretations were performed twice per rater, 4 weeks apart (a total of 160 scorings). Intra-rater test-retest reliability and inter-rater reliability levels were calculated. RESULTS: The most frequent FEES findings in patients with MG before Tensilon application were prominent residues of semi-solids spread all over the hypopharynx in varying locations. The reliability level of the interpretation of the FEES-Tensilon test was excellent regardless of the rater's profession or years of experience with FEES. All four raters showed high inter- and intra-reliability levels in interpreting the FEES-Tensilon test based on residue clearance (kappa = 0.922, 0.981). The degree of residue normalization in the vallecular space after Tensilon application showed the highest inter- and intra-rater reliability level (kappa = 0.863, 0.957) followed by the epiglottis (kappa = 0.813, 0.946) and pyriform sinuses (kappa = 0.836, 0.929). CONCLUSION: Interpretation of the FEES-Tensilon test based on residue severity and degree of Tensilon clearance, especially in the vallecular space, is consistent and reliable.

The bioequivalence of a single intravenous administration of the anesthetic alfaxalone in cyclodextrin versus alfaxalone in cyclodextrin plus preservatives in cats.

To demonstrate the bioequivalence of alfaxalone in cyclodextrin (Reference Product) to a formulation of alfaxalone in cyclodextrin also containing the preservatives ethanol, chlorocresol, and benzethonium chloride (Test Product) when administered for the purpose of inducing anesthesia in the cat. Blinded, single-dose, randomized, two-period, two-sequence, cross-over bioequivalence study with a 7-day washout period between treatments. Twenty-four (12 neutered males and 12 intact females), healthy, adult cats weighing 4.1±0.9 kg. Cats were administered 5 mg/kg IV of alfaxalone in the Reference or Test Product using a randomized cross-over design. One-milliliter venous blood samples were collected at predetermined time points to 12 hr after drug administration to determine alfaxalone plasma concentration over time. Alfaxalone concentrations were determined by a validated analytical testing method using HPLC-MS/MS. Plasma profiles of alfaxalone concentration against time were analyzed by noncompartmental analysis. The pivotal variables for bioequivalence were AUClast and Cmax . Equivalence was achieved if the 90% confidence interval for AUClast and Cmax fell into the asymmetric ±20% interval (0.80-1.25). Physiological variables, quality of anesthesia visual analog scale (VAS) scoring and anesthetic event times were recorded. ANOVA or ANCOVA (single time point), RMANOVA or RMANCOVA (multiple time point) was used for normally distributed data. GLIMMIX was used for nonnormally distributed data. VAS scores were analyzed as for blood bioequivalence data. Variables were evaluated for safety and assessed at alpha = 0.10. Cmax and AUClast for Reference and Test Products were statistically bioequivalent. No physiological variables except for a drug by time interaction for respiratory rate differed between treatment groups, and this difference was not clinically relevant. No anesthetic event times or VAS scores for quality of anesthesia were different between treatment groups. Neither formulation caused pain upon injection. The Reference and Test Products are pharmaceutically bioequivalent formulations when administered as a single intravenous administration for the purpose of induction of anesthesia in cats.

Molecular and biochemical alterations in tubular epithelial cells of patients with isolated methylmalonic aciduria.

Methylmalonic acidurias (MMAurias) are a group of inherited disorders in the catabolism of branched-chain amino acids, odd-chain fatty acids and cholesterol caused by complete or partial deficiency of methylmalonyl-CoA mutase (mut(0) and mut(-) subtype respectively) and by defects in the metabolism of its cofactor 5'-deoxyadenosylcobalamin (cblA, cblB or cblD variant 2 type). A long-term complication found in patients with mut(0) and cblB variant is chronic tubulointerstitial nephritis. The underlying pathomechanism has remained unknown. We established an in vitro model of tubular epithelial cells from patient urine (hTEC; 9 controls, 5 mut(0), 1 cblB). In all human tubular epithelial cell (hTEC) lines we found specific tubular markers (AQP1, UMOD, AQP2). Patient cells showed disturbance of energy metabolism in glycolysis, mitochondrial respiratory chain and Krebs cycle in concert with increased reactive oxygen species (ROS) formation. Electron micrographs indicated increased autophagosome production and endoplasmic reticulum stress, which was supported by positive acridine orange staining and elevated levels of LC3 II, P62 and pIRE1. Screening mTOR signaling revealed a release of inhibition of autophagy. Patient hTEC produced and secreted elevated amounts of the pro-inflammatory cytokine IL8, which was highly correlated with the acridine orange staining. Summarizing, hTEC of MMAuria patients are characterized by disturbed energy metabolism and ROS production that lead to increased autophagy and IL8 secretion.

Towards a Mg Lattice Clock: Observation of the

We optically excite the electronic state 3s3p ^{3}P_{0} in ^{24}Mg atoms, laser cooled and trapped in a magic-wavelength lattice. An applied magnetic field enhances the coupling of the light to the otherwise strictly forbidden transition. We determine the magic wavelength, the quadratic magnetic Zeeman shift, and the transition frequency to be 468.46(21) nm, -206.6(2.0) MHz/T^{2}, and 655 058 646 691(101) kHz, respectively. These are compared with theoretical predictions and results from complementary experiments. We also develop a high-precision relativistic structure model for magnesium, give an improved theoretical value for the blackbody radiation shift, and discuss a clock based on bosonic magnesium.

[Institutionalised dying in Germany. Trends in place of death distribution: home, hospitals and nursing homes]. / Institutionalisiertes Sterben in Deutschland. Trends in der Sterbeortverteilung: zu Hause, Krankenhaus und Pflegeheim.

BACKGROUND: The aim of this study is to identify the degree of institutionalised dying and to assess the differentiation between place of death, be it at a hospital, in a nursing home or at home (with/or without home care), as well as to illustrate trends in the place of death distribution. DATA AND METHODS: Process-produced routine data of the deaths of patients insured with the statutory health insurance "Gmünder Ersatzkasse" (GEK, n = 59,922) are used to calculate distributions of the deceased population (≥ 30 years old) from 2000-2009. RESULTS: In 2009, about 248,000 (29 %) and 598,000 (71 %) people in Germany died at home and in an institution, respectively. During the last 10 years the degree of institutionalised dying has increased by 6 percentage points. Women die more frequently in institutions than men (74 % compared to 67 %). For older age groups, dying in nursing homes becomes more prominent than dying in hospitals. CONCLUSION: The discrepancy between the preferred (at home) and empirically ascertained (institutions) place of death could increase even further as a result of the demographic as well as disease-specific developments in Germany.

Therapeutic safety of high myocardial expression levels of the molecular inotrope S100A1 in a preclinical heart failure model.

Low levels of the molecular inotrope S100A1 are sufficient to rescue post-ischemic heart failure (HF). As a prerequisite to clinical application and to determine the safety of myocardial S100A1 DNA-based therapy, we investigated the effects of high myocardial S100A1 expression levels on the cardiac contractile function and occurrence of arrhythmia in a preclinical large animal HF model. At 2 weeks after myocardial infarction domestic pigs presented significant left ventricular (LV) contractile dysfunction. Retrograde application of AAV6-S100A1 (1.5 × 10(13) tvp) via the anterior cardiac vein (ACV) resulted in high-level myocardial S100A1 protein peak expression of up to 95-fold above control. At 14 weeks, pigs with high-level myocardial S100A1 protein overexpression did not show abnormalities in the electrocardiogram. Electrophysiological right ventricular stimulation ruled out an increased susceptibility to monomorphic ventricular arrhythmia. High-level S100A1 protein overexpression in the LV myocardium resulted in a significant increase in LV ejection fraction (LVEF), albeit to a lesser extent than previously reported with low S100A1 protein overexpression. Cardiac remodeling was, however, equally reversed. High myocardial S100A1 protein overexpression neither increases the occurrence of cardiac arrhythmia nor causes detrimental effects on myocardial contractile function in vivo. In contrast, this study demonstrates a broad therapeutic range of S100A1 gene therapy in post-ischemic HF using a preclinical large animal model.

Autologous stem cell transplantation for elderly patients with newly diagnosed multiple myeloma in the era of novel agents.

BACKGROUND: High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is considered the standard of care for multiple myeloma (MM) patients <65 years. Safety and outcome of ASCT for patients >65 years is currently uncertain, especially since the introduction of novel agents for induction and maintenance therapy. Furthermore, there are no conclusive data available on risk assessment in elderly patients treated with HDT. PATIENTS AND METHODS: We retrospectively analyzed 202 patients ≥60 years with newly diagnosed MM who underwent ASCT at our institution. Patients were stratified by age into three groups (60-64, 65-69 and 70-75 years). For safety assessment, we compared data about hospitalization, hematopoetic reconstitution and early mortality. Remission before and after ASCT was analyzed according to age and application of novel agents. Event-free (EFS) and overall survival (OS) were analyzed to identify impact of age, remission before/after ASCT and maintenance therapy as well as ISS score and cytogenetic aberrations on outcome in elderly patients. RESULTS: The assessment of safety, remission before/after ASCT as well as EFS and OS showed no significant differences between the three groups (median EFS: 60-64 years: 27 months; 65-69 years: 23 months; 70-75 years: 23 months; median OS: not reached). Patients receiving novel agents as part of induction therapy achieved significantly higher nCR + CR rates than patients treated without novel agents. In Cox regression analysis, ISS and cytogenetics as well as remission after ASCT had the highest prognostic impact on EFS and OS. Maintenance therapy was associated with longer EFS in uni- and multivariate analyses. CONCLUSION: ASCT is feasible for selected patients >65 and >70 years without increased mortality. Age at transplantation has no prognostic significance on outcome after ASCT. Novel agents during induction therapy and maintenance therapy improves outcome of older patients eligible for ASCT. ISS and cytogenetic analysis should be carried out routinely for risk assessment.

Imaging for local recurrence of breast cancer.

PURPOSE: Isolated locoregional recurrence of breast cancer (ILRR) and contralateral breast cancer (CBC) affect up to 20% of all breast cancer (BC) patients in the first 20 years after primary diagnosis. Treatment options comprise surgical interventions and further systemic therapies depending on the histological subtype. Patients with hereditary breast or ovarian cancer (HBOC) undergo MRI, mammography, and ultrasound in the aftercare of BC, while non-HBOC (nHBOC) patients do not regularly receive MRI. Since early detection is crucial for morbidity and mortality, the evaluation and constant improvement of imaging methods of the breast is necessary. METHODS: We retrospectively analyzed the data of 1499 former BC patients that received imaging of the breast at a tertiary-care university hospital between 2015 and 2020. The analysis comprised various patient characteristics, such as breast density, age, tumor size and subtype, and their influence on BC detection rates by the different imaging methods. RESULTS: Within the patient sample, 176 individuals (11.7% of former BC patients) were diagnosed with either ILRR or CBC. CBC was observed in 32.4% of patients, while both ILRR and secondary breast cancer occurred in 20.5% and 23.9% of all patients. Sensitivity of MRI, mammography, and ultrasound for recurrent malignancy was 97.9%, 66.3%, and 67.8%, respectively. ILRR and CBC detection rates were similar for patients with and without HBOC history. Lower breast density and larger tumor size increased the detection rates of all imaging modalities. CONCLUSION: In breast cancer survivors, MRI might improve the early detection of ILRR and CBC in both HBOC and nHBOC patients.

Amorfrutin B is an efficient natural peroxisome proliferator-activated receptor gamma (PPARγ) agonist with potent glucose-lowering properties.

AIMS/HYPOTHESIS: The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is an important gene regulator in glucose and lipid metabolism. Unfortunately, PPARγ-activating drugs of the thiazolidinedione class provoke adverse side effects. As recently shown, amorfrutin A1 is a natural glucose-lowering compound that selectively modulates PPARγ. In this study we aimed to characterise, in vitro, a large spectrum of the amorfrutins and similar molecules, which we isolated from various plants. We further studied in vivo the glucose-lowering effects of the so far undescribed amorfrutin B, which featured the most striking PPARγ-binding and pharmacological properties of this family of plant metabolites. METHODS: Amorfrutins were investigated in vitro by binding and cofactor recruitment assays and by transcriptional activation assays in primary human adipocytes and murine preosteoblasts, as well as in vivo using insulin-resistant high-fat-diet-fed C57BL/6 mice treated for 27 days with 100 mg kg(-1) day(-1) amorfrutin B. RESULTS: Amorfrutin B showed low nanomolar binding affinity to PPARγ, and micromolar binding to the isotypes PPARα and PPARß/δ. Amorfrutin B selectively modulated PPARγ activity at low nanomolar concentrations. In insulin-resistant mice, amorfrutin B considerably improved insulin sensitivity, glucose tolerance and blood lipid variables after several days of treatment. Amorfrutin B treatment did not induce weight gain and furthermore showed liver-protecting properties. Additionally, amorfrutins had no adverse effects on osteoblastogenesis and fluid retention. CONCLUSIONS/INTERPRETATION: The application of plant-derived amorfrutins or synthetic analogues thereof constitutes a promising approach to prevent or treat complex metabolic diseases such as insulin resistance or type 2 diabetes.

Origin-Independent Dynamic Polarizability Density from Coupled Cluster Response Theory.

The calculation of the origin-independent density of the dynamic electric dipole polarizability, previously presented for uncorrelated and density functional theory (DFT)-based methods, has been developed and implemented at the coupled cluster singles and doubles (CCSD) level of theory. A pointwise analysis of polarizability densities calculated for a number of molecules at Hartree-Fock (HF) and CCSD clearly shows that the electron correlation effect is much larger than one would argue considering the integrated dipole electric polarizability alone. Large error compensations occur during the integration process, which hide fairly large deviations mainly located in the internuclear regions. The same is observed when calculated CCSD and B3LYP polarizability densities are compared, with the remarkable feature that positive/negative deviations between CCSD and HF reverse sign, becoming negative/positive when comparing CCSD to B3LYP.

Potential of employing a quantum iterative reconstruction algorithm for ultra-high-resolution photon-counting detector CT of the hip.

INTRODUCTION: This study investigated the image quality of a new quantum iterative reconstruction algorithm (QIR) for high resolution photon-counting CT of the hip. METHODS: Using a first-generation photon-counting CT scanner, five cadaveric specimens were examined with ultra-high-resolution protocols matched for radiation dose. Images were post-processed with a sharp convolution kernel and five different strength levels of iterative reconstruction (QIR 0 - QIR 4). Subjective image quality was rated independently by three radiologists on a five-point scale. Intraclass correlation coefficients (ICC) were computed for assessing interrater agreement. Objective image quality was evaluated by means of contrast-to-noise-ratios (CNR) in bone and muscle tissue. RESULTS: For osseous tissue, subjective image quality was rated best for QIR 2 reformatting (median 5 [interquartile range 5-5]). Contrarily, for soft tissue, QIR 4 received the highest ratings among compared strength levels (3 [3-4]). Both ICCbone (0.805; 95% confidence interval 0.711-0.877; p < 0.001) and ICCmuscle (0.885; 0.824-0.929; p < 0.001) suggested good interrater agreement. CNR in bone and muscle tissue increased with ascending strength levels of iterative reconstruction with the highest results recorded for QIR 4 (CNRbone 29.43 ± 2.61; CNRmuscle 8.09 ± 0.77) and lowest results without QIR (CNRbone 3.90 ± 0.29; CNRmuscle 1.07 ± 0.07) (all p < 0.001). CONCLUSION: Reconstructing photon-counting CT data with an intermediate QIR strength level appears optimal for assessment of osseous tissue, whereas soft tissue analysis benefitted from applying the highest strength level available. IMPLICATIONS FOR PRACTICE: Quantum iterative reconstruction technique can enhance image quality by significantly reducing noise and improving CNR in ultra-high resolution CT imaging of the hip.

Orodispersible films - Recent developments and new applications in drug delivery and therapy.

Orodispersible films (ODF) are innovative drug formulations that introduce a promising approach to pharmacotherapy. They represent single- or multi-layer polymer films that show sufficient stability but disintegrate easily. Often no water is needed for ingestion. Therefore, ODF are suitable for patients with swallowing difficulties such as elderly people, children, or patients with restricted transport in the gastrointestinal tract. Also, to avoid the first-pass effect when the drug is already absorbed via the mucosa. Initially developed as niche products ODFs are currently the subject of industrial and university research as dosage forms for improved application and compliance for medical treatment of a multitude of different diseases. An interesting aspect is that ODF can also be produced in an individualized way. This can support the trend toward personalized medicine. Here, we provide at first an overview of the historical background, characterization, and composition of ODFs. Subsequently, technical aspects of the manufacturing process, including three-dimensional printing technology and inkjet printing will be reviewed. As ODFs are promising drug delivery systems for customized small-scale pharmacy preparations, we place particular emphasis on product examples giving the possibility for individualization for their consumers. Finally, we summarize formulations, applications in development, limitations, and the current patent situation.

Lattice fluctuations at a double phonon frequency with and without squeezing: an exactly solvable model of an optically excited quantum dot.

Time-dependent lattice fluctuations of an optically excited strongly confined quantum dot are investigated with the aim to analyze the characteristics commonly used for identifying the presence of squeezed phonon states. It is demonstrated that the appearance of fluctuations oscillating with twice the phonon frequency, commonly regarded as a clear indication of squeezed states, cannot be considered as such. The source of the discrepancy with earlier investigations is discussed. Conditions for generating a squeezed state by using a two-pulse excitation are analyzed.

The genomic response of the Drosophila embryo to JNK signaling.

During Drosophila development, the Jun N-terminal kinase signal transduction pathway regulates morphogenetic tissue closure movements that involve cell shape changes and reorganization of the actin cytoskeleton. We analyzed the genome-wide transcriptional response to activation of the JNK pathway in the Drosophila embryo by serial analysis of gene expression (SAGE) and identified loci encoding cell adhesion molecules and cytoskeletal regulators as JNK responsive genes. The role of one of the upregulated genes, chickadee (chic), encoding a Drosophila profilin, in embryogenesis was analyzed genetically. chic-deficient embryos fail to execute the JNK-mediated cytoskeletal rearrangements during dorsal closure. This study demonstrates a transcriptional mechanism of cytoskeletal regulation and establishes SAGE as an advantageous approach for genomic experiments in the fruitfly.

Long-term exposure of human proximal tubule cells to hydroxycobalamin[c-lactam] as a possible model to study renal disease in methylmalonic acidurias.

Dysfunction of proximal tubules resulting in tubulointerstitial nephritis and chronic renal failure is a frequent long-term complication of methylmalonic acidurias. However, the underlying pathomechanisms have not yet been extensively studied owing to the lack of suitable in vitro and in vivo models. Application of hydroxycobalamin[c-lactam] has been shown to inhibit the metabolism of hydroxycobalamin and, thereby, to induce methylmalonic aciduria in rats, oligodendrocytes, and rat hepatocytes. Our study characterizes the biochemical and bioenergetic effects of long-term exposure of human proximal tubule cells to hydroxycobalamin[c-lactam], aiming to establish a novel in vitro model for the renal pathogenesis of methylmalonic acidurias. Incubation of human proximal tubule cells with hydroxycobalamin[c-lactam] and propionic acid resulted in a strong, time-dependent intra- and extracellular accumulation of methylmalonic acid. Bioenergetic studies of respiratory chain enzyme complexes revealed an increase of complex II-IV activity after 2 weeks and an increase of complex I and IV activity as well as a decrease of complex II and III activity after 3 weeks of incubation. In addition, human proximal tubule cells displayed reduced glutathione content after the exposure to hydroxycobalamin[c-lactam] and propionic acid.

Mechanisms of potassium- and capsaicin-induced axonal calcitonin gene-related peptide release: involvement of L- and T-type calcium channels and TRPV1 but not sodium channels.

We have previously shown that capsaicin, noxious heat, protons and potassium ions (K(+)) induce a graded, calcium- and receptor-dependent increase of immunoreactive calcitonin gene-related peptide (iCGRP) release from isolated rat sciatic axons. Morphological evidence for axonal vesicular exocytosis has also been presented. Here we determine the differential contribution of voltage-gated calcium and sodium channels to high extracellular potassium and capsaicin-induced iCGRP secretion. Blockade of L-type calcium channels significantly decreased the K(+)-induced axonal response (nimodipine (10 microM) by 66% and methoxyverapamil, D600 (50 microM), by 77%). Interestingly, however, D600 was unable to reduce the capsaicin-induced iCGRP release. Omega-Conotoxin GVIA (1 microM), a N-type blocker, and omega-agatoxin TK (0.1 microM), a P/Q-type blocker, had no significant effect. Also the anticonvulsant gabapentin (50 microM and 100 microM), reported to impede calcium channels, was ineffective. Inhibition of low threshold T-type calcium channels by mibefradil (10 microM) significantly reduced potassium (by 47%) but not capsaicin-stimulated iCGRP release. Reduction of total sodium channel conductance by tetrodotoxin (1 microM), lidocaine (10 microM, 50 microM or 500 microM) or by replacement of extracellular sodium with choline-chloride did not result in a reduction of either potassium- or capsaicin-induced axonal iCGRP release. These results suggest that slow depolarization by high extracellular potassium activates axonal low threshold (T-type) as well as high threshold-activated (L-type) voltage-gated calcium channels to mediate iCGRP release, and that capsaicin-induced release is largely dependent on calcium influx through TRPV1. Action potential generation and propagation are not required for axonal release mechanisms.

Pathogenesis of CNS involvement in disorders of amino and organic acid metabolism.

Inherited disorders of amino and organic acid metabolism have a high cumulative frequency, and despite heterogeneous aetiology and varying clinical presentation, the manifestation of neurological disease is common. It has been demonstrated for some of these diseases that accumulating pathological metabolites are directly involved in the manifestation of neurological disease. Various pathomechanisms have been suggested in different in vitro and in vivo models including an impairment of brain energy metabolism, an imbalance of excitatory and inhibitory neurotransmission, altered transport across the blood-brain barrier and between glial cells and neurons, impairment of myelination and disturbed neuronal efflux of metabolic water. This review summarizes recent knowledge on pathomechanisms involved in phenylketonuria, glutaric aciduria type I, succinic semialdehyde dehydrogenase deficiency and aspartoacylase deficiency with examples, highlighting general as well as disease-specific concepts and their putative impact on treatment.