Dent disease: A window into calcium and phosphate transport

This review examines calcium and phosphate transport in the kidney through the lens of the rare X-linked genetic disorder Dent disease. Dent disease type 1 (DD1) is caused by mutations in the CLCN5 gene encoding ClC-5, a Cl- /H+ antiporter localized to early endosomes of the proximal tubule (PT). Phenotypic features commonly include low molecular weight proteinuria (LMWP), hypercalciuria, focal global sclerosis and chronic kidney disease; calcium nephrolithiasis, nephrocalcinosis and hypophosphatemic rickets are less commonly observed. Although it is not surprising that abnormal endosomal function and recycling in the PT could result in LMWP, it is less clear how ClC-5 dysfunction disturbs calcium and phosphate metabolism. It is known that the majority of calcium and phosphate transport occurs in PT cells, and PT endocytosis is essential for calcium and phosphorus reabsorption in this nephron segment. Evidence from ClC-5 KO models suggests that ClC-5 mediates parathormone endocytosis from tubular fluid. In addition, ClC-5 dysfunction alters expression of the sodium/proton exchanger NHE3 on the PT apical surface thus altering transcellular sodium movement and hence paracellular calcium reabsorption. A potential role for NHE3 dysfunction in the DD1 phenotype has never been investigated, either in DD models or in patients with DD1, even though patients with DD1 exhibit renal sodium and potassium wasting, especially when exposed to even a low dose of thiazide diuretic. Thus, insights from the rare disease DD1 may inform possible underlying mechanisms for the phenotype of hypercalciuria and idiopathic calcium stones

Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons

The perspective of neuroinflammation as an epiphenomenon following neuron damage is being replaced by the awareness of glia and their importance in neural functions and disorders. Systemic inflammation generates signals that communicate with the brain and leads to changes in metabolism and behavior, with microglia assuming a pro-inflammatory phenotype. Identification of potential peripheral-to-central cellular links is thus a critical step in designing effective therapeutics. Mast cells may fulfill such a role. These resident immune cells are found close to and within peripheral nerves and in brain parenchyma/meninges, where they exercise a key role in orchestrating the inflammatory process from initiation through chronic activation. Mast cells and glia engage in crosstalk that contributes to accelerate disease progression; such interactions become exaggerated with aging and increased cell sensitivity to stress. Emerging evidence for oligodendrocytes, independent of myelin and support of axonal integrity, points to their having strong immune functions, innate immune receptor expression, and production/response to chemokines and cytokines that modulate immune responses in the central nervous system while engaging in crosstalk with microglia and astrocytes. In this review, we summarize the findings related to our understanding of the biology and cellular signaling mechanisms of neuroinflammation, with emphasis on mast cell-glia interactions

Concerns about anti-angiogenic treatment in patients with glioblastoma multiforme

BACKGROUND: The relevance of angiogenesis inhibition in the treatment of glioblastoma multiforme (GBM) should be considered in the unique context of malignant brain tumours. Although patients benefit greatly from reduced cerebral oedema and intracranial pressure, this important clinical improvement on its own may not be considered as an anti-tumour effect. DISCUSSION: GBM can be roughly separated into an angiogenic component, and an invasive or migratory component. Although this latter component seems inert to anti-angiogenic therapy, it is of major importance for disease progression and survival. We reviewed all relevant literature. Published data support that clinical symptoms are tempered by anti-angiogenic treatment, but that tumour invasion continues. Unfortunately, current imaging modalities are affected by anti-angiogenic treatment too, making it even harder to define tumour margins. To illustrate this we present MRI, biopsy and autopsy specimens from bevacizumab-treated patients. Moreover, while treatment of other tumour types may be improved by combining chemotherapy with anti-angiogenic drugs, inhibiting angiogenesis in GBM may antagonise the efficacy of chemotherapeutic drugs by normalising the blood-brain barrier function. SUMMARY: Although angiogenesis inhibition is of considerable value for symptom reduction in GBM patients, lack of proof of a true anti-tumour effect raises concerns about the place of this type of therapy in the treatment of GBM

Advances in MRI Assessment of Gliomas and Response to Anti-VEGF Therapy

Bevacizumab is thought to normalize tumor vasculature and restore the blood–brain barrier, decreasing enhancement and peritumoral edema. Conventional measurements of tumor response rely upon dimensions of enhancing tumor. After bevacizumab treatment, glioblastomas are more prone to progress as nonenhancing tumor. The RANO (Response Assessment in Neuro-Oncology) criteria for glioma response use fluid-attenuated inversion recovery (FLAIR)/T2 hyperintensity as a surrogate for nonenhancing tumor; however, nonenhancing tumor can be difficult to differentiate from other causes of FLAIR/T2 hyperintensity (eg, radiation-induced gliosis). Due to these difficulties, recent efforts have been directed toward identifying new biomarkers that either predict treatment response or accurately measure response of both enhancing and nonenhancing tumor shortly after treatment initiation. This will allow for earlier treatment decisions, saving patients from the adverse effects of ineffective therapies while allowing them to try alternative therapies sooner. An active area of research is the use of physiologic imaging, which can potentially detect treatment effects before changes in tumor size are evident

Tracking of an electron beam through the solar corona with LOFAR

© ESO 2018. The Sun's activity leads to bursts of radio emission, among other phenomena. An example is type-III radio bursts. They occur frequently and appear as short-lived structures rapidly drifting from high to low frequencies in dynamic radio spectra. They are usually interpreted as signatures of beams of energetic electrons propagating along coronal magnetic field lines. Here we present novel interferometric LOFAR (LOw Frequency ARray) observations of three solar type-III radio bursts and their reverse bursts with high spectral, spatial, and temporal resolution. They are consistent with a propagation of the radio sources along the coronal magnetic field lines with nonuniform speed. Hence, the type-III radio bursts cannot be generated by a monoenergetic electron beam, but by an ensemble of energetic electrons with a spread distribution in velocity and energy. Additionally, the density profile along the propagation path is derived in the corona. It agrees well with three-fold coronal density model by (1961, ApJ, 133, 983)

A case report of delayed cortical infarction adjacent to sulcal clots after traumatic subarachnoid hemorrhage in the absence of proximal vasospasm

Background Cortical ischemic lesions represent the predominant pathomorphological pattern of focal lesions after aneurysmal subarachnoid hemorrhage (aSAH). Autopsy studies suggest that they occur adjacent to subarachnoid blood and are related to spasm of small cortical rather than proximal arteries. Recent clinical monitoring studies showed that cortical spreading depolarizations, which induce cortical arterial spasms, are involved in lesion development. If subarachnoid blood induces adjacent cortical lesions, it would be expected that (i) they also develop after traumatic subarachnoid hemorrhage (tSAH), and (ii) lesions after tSAH can occur in absence of angiographic vasospasm, as was found for aSAH. Case presentation An 86-year-old woman was admitted to our hospital with fluctuating consciousness after hitting her head during a fall. The initial computed tomography (CT) was significant for tSAH in cortical sulci. On day 8, the patient experienced a secondary neurological deterioration with reduced consciousness and global aphasia. Whereas the CT scan on day 9 was still unremarkable, magnetic resonance imaging (MRI) on day 10 revealed new cortical laminar infarcts adjacent to sulcal blood clots. Proximal vasospasm was ruled out using MR and CT angiography and Doppler sonography. CT on day 14 confirmed the delayed infarcts. Conclusions We describe a case of delayed cortical infarcts around sulcal blood clots after tSAH in the absence of proximal vasospasm, similar to results found previously for aSAH. As for aSAH, this case suggests that assessment of angiographic vasospasm is not sufficient to screen for risk of delayed infarcts after tSAH. Electrocorticography is suggested as a complementary method to monitor the hypothesized mechanism of spreading depolarizations