Unlike most receptors, Notch serves as both the receiver and direct transducer of signaling events. Activation can be mediated by one of five membrane-bound ligands of either the Delta-like (-1, -2, -4) or Jagged/Serrate (-1, -2) families. Alternatively, dissociation of the Notch heterodimer with consequent activation can also be mediated experimentally by calcium chelators or by mutations that destabilize the Notch1 heterodimer, such as in the human disease T cell acute lymphoblastic leukemia. Here we show that MAGP-2, a protein present on microfibrils, can also interact with the EGF-like repeats of Notch1. Co-expression of MAGP-2 with Notch1 leads to both cell surface release of the Notch1 extracellular domain and subsequent activation of Notch signaling. Moreover, we demonstrate that the C-terminal domain of MAGP-2 is required for binding and activation of Notch1. Based on the high level of homology, we predicted and further showed that MAGP-1 can also bind to Notch1, cause the release of the extracellular domain, and activate signaling. Notch1 extracellular domain release induced by MAGP-2 is dependent on formation of the Notch1 heterodimer by a furinlike cleavage, but does not require the subsequent ADAM metalloprotease cleavage necessary for production of the Notch signaling fragment. Together these results demonstrate for the first time that the microfibrillar proteins MAGP-1 and MAGP-2 can function outside of their role in elastic fibers to activate a cellular signaling pathway.Notch signaling is best known for its role in cell fate determination and is critical for regulating multiple cellular processes in many different tissues, including those of the nervous, hematopoietic, and vascular systems (1). Controlled by membrane-tethered ligands on apposing cells, ligand binding initiates canonical Notch signaling and leads to the proteolytic release of the Notch intracellular domain (NICD).2 The NICD fragment travels to the nucleus, interacts with a DNA-binding protein CSL (CBF1/Su(H)/LAG-1), and activates expression of target genes such as HES1.At least three proteolytic events are required for Notch activation through CSL. The first cleavage is ligand-independent and occurs during maturation of the co-linear Notch protein. Either during trafficking or at the cell surface, Notch is cleaved by a furin-like convertase into two fragments, the extracellular domain (N EC ) and the transmembrane-anchored intracellular domain (N TM ), that remain associated through non-covalent interactions (2-4). This "heterodimer" is the predominant form of Notch on the plasma membrane and is required for ligand-induced CSL-dependent Notch signaling (4). Accordingly, ligand engagement by the heterodimeric Notch receptor leads to sequential ADAM and ␥-secretase cleavage events that facilitate the release of NICD from its membrane tether to activate signaling (5, 6).Underscoring the importance of Notch signaling is the finding that more than 50% of T-ALL patient samples tested so far carry activating mutations of Notch1 (N1) ...

Hemolytic uremic syndrome (HUS) can be classified as typical and atypical, and the treatment recommendations currently differ between the 2 types. Eculizumab is recommended as first-line treatment for atypical HUS; however, its use in typical HUS has been controversial. We report a case of a 10-year-old male with severe neurologic impairment who was successfully treated with eculizumab, which was started 4 days after onset of neurologic symptoms. Our case supports the use of eculizumab in typical HUS with neurologic involvement, even when given later in the course, as the pathophysiology of typical HUS has been shown to involve activation of the complement pathway, similar to atypical HUS. Further studies are required to establish the efficacy and duration of eculizumab use in this patient population.

Rhabdomyolysis is diagnosed with creatinine kinase (CK) elevation beyond 1000 U/L or ten times above the normal upper limit. Severe episodes can be fatal from electrolyte imbalance, acute renal failure, and disseminated intravascular coagulation. A 13-month-old child was admitted with a CK of 82,090 U/L in the setting of respiratory tract infection-related hyperthermia of 106.9° farenheit. His medical history was significant for prematurity, dystonia, and recurrent rhabdomyolysis. His home medications clonazepam, clonidine, and baclofen were continued upon admission. He exhibited uncontrolled dystonia despite treatment for dystonia. Therefore, sedative infusions and forced alkaline diuresis were begun to prevent heme pigment-induced renal injury. Despite these interventions, his CK peaked at 145,920 U/L, which is rarely reported in this age group. The patient also developed pulmonary edema despite diuresis and required mechanical ventilation. Sedative infusions were not enough for dystonia management, and he needed the addition of a neuromuscular blocking infusion. He finally responded to these interventions, and the CK normalized after a month. He required a month of mechanical ventilation and two and a half months of hospitalization and extensive rehabilitation. We were able to avert renal replacement therapy despite pulmonary edema and an estimated glomerular filtration rate nadir of 21 mL/min/1.73 m2 based on the bedside Schwartz formula. He made a complete recovery and was discharged home. His growth and development were satisfactory for two years after that event. His extensive diagnostic workup was negative. Unfortunately, he died from septic and cardiogenic shock with mild rhabdomyolysis two years later. Prompt recognition, early institution of appropriate therapies, identification of underlying disease, and triggering events are pivotal in rhabdomyolysis management. Evidence-based guidelines are needed in this context.

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