Efficacy of Human Adipose Tissue-Derived Stem Cells on Neonatal Bilirubin Encephalopathy in Rats

Kernicterus is a neurological syndrome associated with indirect bilirubin accumulation and damages to the basal ganglia, cerebellum and brain stem nuclei particularly the cochlear nucleus. To mimic haemolysis in a rat model such that it was similar to what is observed in a preterm human, we injected phenylhydrazine in 7-day-old rats to induce haemolysis and then infused sulfisoxazole into the same rats at day 9 to block bilirubin binding sites in the albumin. We have investigated the effectiveness of human adiposity-derived stem cells as a therapeutic paradigm for perinatal neuronal repair in a kernicterus animal model. The level of total bilirubin, indirect bilirubin, brain bilirubin and brain iron was significantly increased in the modelling group. There was a significant decreased in all severity levels of the auditory brainstem response test in the two modelling group. Akinesia, bradykinesia and slip were significantly declined in the experience group. Apoptosis in basal ganglia and cerebellum were significantly decreased in the stem cell-treated group in comparison to the vehicle group. All severity levels of the auditory brainstem response tests were significantly decreased in 2-month-old rats. Transplantation results in the substantial alleviation of walking impairment, apoptosis and auditory dysfunction. This study provides important information for the development of therapeutic strategies using human adiposity-derived stem cells in prenatal brain damage to reduce potential sensori motor deficit.     

Impact of baseline platelet count in patients undergoing primary percutaneous coronary intervention in acute myocardial infarction (from the CADILLAC trial)

Despite the well-recognized role of platelets in the pathogenesis of acute myocardial infarction (AMI) and in the vascular responses to angioplasty, the relation between platelet count and outcomes after primary percutaneous coronary intervention (PCI) in AMI is unknown. We therefore determined the effect of baseline platelet count on clinical and angiographic outcomes of patients with AMI undergoing primary PCI. In the prospective, randomized CADILLAC trial, platelet count on admission was available in 2,021 of 2,082 patients (97.0%). Angiographic results and outcomes at 30 days and 1 year were stratified by quartiles of platelet count. Median platelet count was 231 x 10(9)/L (range 38 to 709). Primary PCI angiographic success rates were independent of platelet count. The 30-day incidence of target vessel thrombosis or reocclusion increased steadily across the higher quartiles of baseline platelet count (0.2%, 0.6%, 1.0%, and 2.0%, p = 0.027). At 1 year, patients with a baseline platelet count >or=234 versus <234 x 10(9)/L had higher rates of death or reinfarction (8.9% vs 4.5%, p <0.0001), death (5.8% vs 3.1%, p = 0.002), and reinfarction (3.4% vs 1.6%, p = 0.008). By multivariable analysis, a higher baseline platelet count was the strongest predictor of 1-year death or reinfarction (hazard ratio [HR] per 10,000 increase in platelet count 1.02, 95% confidence interval [CI] 1.02 to 1.07, p <0.0001) and independently predicted reinfarction (HR 1.06, 95% CI 1.02 to 1.09, p = 0.002) and cardiac mortality (HR 1.03, 95% CI 1.00 to 1.06, p = 0.055) at 1 year. In conclusion, a higher baseline platelet count in patients with AMI is a powerful independent predictor of death and reinfarction within the first year after primary PCI.     

Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function

Multiple independent mutations in neuroligin genes were identified in patients with familial autism, including the R451C substitution in neuroligin-3 (NL3). Previous studies showed that NL3(R451C) knock-in mice exhibited modestly impaired social behaviors, enhanced water maze learning abilities, and increased synaptic inhibition in the somatosensory cortex, and they suggested that the behavioral changes in these mice may be caused by a general shift of synaptic transmission to inhibition. Here, we confirm that NL3(R451C) mutant mice behaviorally exhibit social interaction deficits and electrophysiologically display increased synaptic inhibition in the somatosensory cortex. Unexpectedly, however, we find that the NL3(R451C) mutation produced a strikingly different phenotype in the hippocampus. Specifically, in the hippocampal CA1 region, the NL3(R451C) mutation caused an ～1.5-fold increase in AMPA receptor-mediated excitatory synaptic transmission, dramatically altered the kinetics of NMDA receptor-mediated synaptic responses, induced an approximately twofold up-regulation of NMDA receptors containing NR2B subunits, and enhanced long-term potentiation almost twofold. NL3 KO mice did not exhibit any of these changes. Quantitative light microscopy and EM revealed that the NL3(R451C) mutation increased dendritic branching and altered the structure of synapses in the stratum radiatum of the hippocampus. Thus, in NL3(R451C) mutant mice, a single point mutation in a synaptic cell adhesion molecule causes context-dependent changes in synaptic transmission; these changes are consistent with the broad impact of this mutation on murine and human behaviors, suggesting that NL3 controls excitatory and inhibitory synapse properties in a region- and circuit-specific manner.     

Onychomadesis in a patient with immunoglobulin class switch recombination deficiency

Immunoglobulin class switch recombination deficiencies (Ig CSR deficiencies) or Hyper IgM syndromes (HIGM) are a group of primary immunodeficiency diseases, characterized by defective CD40 signaling of B cells, resulting in reduced CSR and somatic hypermutation. The affected patients are characterized by low serum levels of IgG and IgA, and normal or elevated levels of IgM, which lead to an increased susceptibility to infections. We describe a 3 year-old boy with frequent bacterial infections of the skin and respiratory tract, mucosal ulcers, and diarrhea. He experienced onychomadesis of both fingernails and toenails during a recent bacterial infection. Quantitative immunoglobulin measurements revealed high levels of serum IgM and very low levels of IgG, IgA, and IgE. Clinical and immunologic studies supported the diagnosis of HIGM. Exclusion of CD40L, CD40, AID and UNG genes by molecular analysis in this patient may suggest a new form of selective CSR deficiency.