Notch 1-deficient common lymphoid precursors adopt a B cell fate in the thymus.

We have recently reported that Notch 1, a member of the Notch multigene family, is essential for the development of murine T cells. Using a mouse model in which Notch 1 is inactivated in bone marrow (BM) precursors we have shown that B cells instead of T cells are found in the thymus of BM chimeras. However, it is not clear whether these B cells develop by default from a common lymphoid precursor due to the absence of Notch 1 signaling, or whether they arise as a result of perturbed migration of BM-derived B cells and/or altered homeostasis of normal resident thymic B cells. In this report we show that Notch 1-deficient thymic B cells resemble BM B cells in phenotype and turnover kinetics and are located predominantly in the medulla and corticomedullary junction. Peripheral blood lymphocyte analysis shows no evidence of recirculating Notch1(-/)- BM B cells. Furthermore, lack of T cell development is not due to a failure of Notch1(-/)- precursors to home to the thymus, as even after intrathymic reconstitution with BM cells, B cells instead of T cells develop from Notch 1-deficient precursors. Taken together, these results provide evidence for de novo ectopic B cell development in the thymus, and support the hypothesis that in the absence of Notch 1 common lymphoid precursors adopt the default cell fate and develop into B cells instead.

Endeavors Update, Iowa Medicaid Enterprise, Vol. 1, Issue 1 September 30, 2010

The Iowa Medicaid Enterprise (IME) is an endeavor, started in 2005, to unite State staff with “best of breed” contractors into a performance-based model for administration of the Medicaid program.

Endeavors Update, Iowa Medicaid Enterprise, Vol. 1, Issue 2 October 28, 2010

The Iowa Medicaid Enterprise (IME) is an endeavor, started in 2005, to unite State staff with “best of breed” contractors into a performance-based model for administration of the Medicaid program.

Endeavors Update, Iowa Medicaid Enterprise, Vol. 1, Issue 8 March, 22, 2011

The Iowa Medicaid Enterprise (IME) is an endeavor, started in 2005, to unite State staff with “best of breed” contractors into a performance-based model for administration of the Medicaid program.

Endeavors Update, Iowa Medicaid Enterprise, Vol. 1, Issue 3, November 30, 2010

The Iowa Medicaid Enterprise (IME) is an endeavor, started in 2005, to unite State staff with “best of breed” contractors into a performance-based model for administration of the Medicaid program.

Endeavors Update, Iowa Medicaid Enterprise, Vol. 1, Issue 4, December 23, 2010

The Iowa Medicaid Enterprise (IME) is an endeavor, started in 2005, to unite State staff with “best of breed” contractors into a performance-based model for administration of the Medicaid program.

Endeavors Update, Iowa Medicaid Enterprise, Vol. 1, Issue 5, January 27, 2011

The Iowa Medicaid Enterprise (IME) is an endeavor, started in 2005, to unite State staff with “best of breed” contractors into a performance-based model for administration of the Medicaid program.

Endeavors Update, Iowa Medicaid Enterprise: Early Addition, Vol. 1, Issue 6, February 15, 2011

The Iowa Medicaid Enterprise (IME) is an endeavor, started in 2005, to unite State staff with “best of breed” contractors into a performance-based model for administration of the Medicaid program.

Endeavors Update, Iowa Medicaid Enterprise: Late Addition, Vol. 1, Issue 7, February 24, 2011

The Iowa Medicaid Enterprise (IME) is an endeavor, started in 2005, to unite State staff with “best of breed” contractors into a performance-based model for administration of the Medicaid program.

Endeavors Update, Iowa Medicaid Enterprise, Vol. 1, Issue 9 April 26, 2011

The Iowa Medicaid Enterprise (IME) is an endeavor, started in 2005, to unite State staff with “best of breed” contractors into a performance-based model for administration of the Medicaid program.

Endeavors Update, Iowa Medicaid Enterprise, Vol. 1, Issue 10 May 26, 2011

The Iowa Medicaid Enterprise (IME) is an endeavor, started in 2005, to unite State staff with “best of breed” contractors into a performance-based model for administration of the Medicaid program.

Endeavors Update, Iowa Medicaid Enterprise, Vol. 1, Issue 11 June 23, 2011

The Iowa Medicaid Enterprise (IME) is an endeavor, started in 2005, to unite State staff with “best of breed” contractors into a performance-based model for administration of the Medicaid program.

14.1T magnetic resonance spectroscopic evaluation of metabolic changes in the mouse striatum following transient middle cerebral artery occlusion

Magnetic resonance imaging (MRI) and spectroscopy (MRS) allow establishing theanatomical evolution and neurochemical profiles of ischemic lesions. However onlylimited MRS studies have been reported to-date in mice due to the challenges ofMRS in small organs. The aim of the current work was to study the neurochemicaland imaging sequelae of ischemic stroke in a mouse model in a horizontal bore14.1 Tesla system.ICR-CD1 mice were subjected to 30 minute transient middle cerebral artery occlusion.The extent of the lesion was determined by MRI. The neurochemical profileconsisting of the concentrations of 22 metabolites was measured longitudinallyfollowing the recovery from ischemia at 3, 8 and 24h in the striatum.Our model produced very reproducible striatal lesions which began to appear onT2-weighted images 8h after ischemia. At 24h, they were well established andtheir size correlated with lesions measured by histology. Profound changes couldbe observed in the neurochemical profiles of the core of the striatal lesions as earlyas 3h post-ischemia, in particular, we observed elevated lactate levels, decreases inthe putative neuronal marker N-acetyl-aspartate and in glutamate, and a transienttwo-fold glutamine increase, likely linked to excitotoxic release of glutamate andconversion to glutamine. With further ischemia evolution, other changes appearedat later time-points, mainly decreases of metabolites, consistent with disruption ofcellular function. It is interesting to note that glutamine tended to return to basallevels at 24h.We conclude that early changes in markers of energy metabolism, glutamate excitotoxicityand neuronal viability can be detected with high precision non-invasively inmice following stroke. Such investigations should lead to a better understanding andinsight into the sequential early changes in the brain parenchyma after ischemia,which could be used e.g. for identifying new targets for neuroprotection.

Insulin-Like growth-factor 1 myocardial expression decreases in chronic alcohol consumption

Background Chronic alcohol ingestion may cause severe biochemical and pathophysiological derangements to skeletal muscle. Unfortunately, these alcohol-induced events may also prime skeletal muscle for worsened, delayed, or possibly incomplete repair following acute injury. As alcoholics may be at increased risk for skeletal muscle injury, our goals were to identify the effects of chronic alcohol ingestion on components of skeletal muscle regeneration. To accomplish this, age- and gender-matched C57Bl/6 mice were provided normal drinking water or water that contained 20% alcohol (v/v) for 1820 wk. Subgroups of mice were injected with a 1.2% barium chloride (BaCl2) solution into the tibialis anterior (TA) muscle to initiate degeneration and regeneration processes. Body weights and voluntary wheel running distances were recorded during the course of recovery. Muscles were harvested at 2, 7 or 14 days post-injection and assessed for markers of inflammation and oxidant stress, fiber cross-sectional areas, levels of growth and fibrotic factors, and fibrosis. Results Body weights of injured, alcohol-fed mice were reduced during the first week of recovery. These mice also ran significantly shorter distances over the two weeks following injury compared to uninjured, alcoholics. Injured TA muscles from alcohol-fed mice had increased TNFα and IL6 gene levels compared to controls 2 days after injury. Total protein oxidant stress and alterations to glutathione homeostasis were also evident at 7 and 14 days after injury. Ciliary neurotrophic factor (CNTF) induction was delayed in injured muscles from alcohol-fed mice which may explain, in part, why fiber cross-sectional area failed to normalize 14 days following injury. Gene levels of TGFβ1 were induced early following injury before normalizing in muscle from alcohol-fed mice compared to controls. However, TGFβ1 protein content was consistently elevated in injured muscle regardless of diet. Fibrosis was increased in injured, muscle from alcohol-fed mice at 7 and 14 days of recovery compared to injured controls. Conclusions Chronic alcohol ingestion appears to delay the normal regenerative response following significant skeletal muscle injury. This is evidenced by reduced cross-sectional areas of regenerated fibers, increased fibrosis, and altered temporal expression of well-described growth and fibrotic factors.

Sh3tc2 deficiency affects neuregulin-1/ErbB signaling.

Mutations in SH3TC2 trigger autosomal recessive demyelinating Charcot-Marie-Tooth type 4C (CMT4C) neuropathy. Sh3tc2 is specifically expressed in Schwann cells and is necessary for proper myelination of peripheral axons. In line with the early onset of neuropathy observed in patients with CMT4C, our analyses of the murine model of CMT4C revealed that the myelinating properties of Sh3tc2-deficient Schwann cells are affected at an early stage. This early phenotype is associated with changes in the canonical Nrg1/ErbB pathway involved in control of myelination. We demonstrated that Sh3tc2 interacts with ErbB2 and plays a role in the regulation of ErbB2 intracellular trafficking from the plasma membrane upon Nrg1 activation. Interestingly, both the loss of Sh3tc2 function in mice and the pathological mutations present in CMT4C patients affect ErbB2 internalization, potentially altering its downstream intracellular signaling pathways. Altogether, our results indicate that the molecular mechanism for the axonal size sensing is disturbed in Sh3tc2-deficient myelinating Schwann cells, thus providing a novel insight into the pathophysiology of CMT4C neuropathy.