A Rose by Any Other Name? The Potential Consequences of Microglial Heterogeneity During CNS Health and Disease

Microglial activation and macrophage infiltration into the CNS are common features of CNS autoimmune disease and of chronic neurodegenerative diseases. Because these cells largely express an overlapping set of common macrophage markers, it has been difficult to separate their respective contributions to disease onset and progression. This problem is further confounded by the many types of macrophages that have been termed microglia. Several approaches, ranging from molecular profiling of isolated cells to the generation of irradiation chimeric rodent models, are now beginning to generate rudimentary definitions distinguishing the various types of microglia and macrophages found within the CNS and the potential roles that these cells may play in health and disease.     

Ocular manifestations of Donohue's syndrome.

INTRODUCTION: Donohue's syndrome, also known as Leprechaunism, is a rare autosomal recessive disease that manifests at birth with symptoms of endocrine dysfunction. Metabolic characteristics of the disease include postprandial hyperglycemia, fasting hypoglycemia, insulin resistance, hyperinsulinemia, and failure to thrive. The physical features most often associated with this condition include hypertrichosis, pachyderma, acanthosis nigricans, prominent genitalia, and elfin-like facial characteristics of prominent eyes, wide nostrils, thick lips, and large, low-set ears. Not only is this syndrome rare, but it often results in infant and early childhood mortality. The literature regarding ocular manifestations is limited. CASE REPORT: We present a case of a 29-year-old male with Donohue's syndrome and significant ocular findings including a subluxated mature cataract, retinal detachment, high myopia, and optic atrophy. DISCUSSION: These ocular sequelae are discussed with regard to the noted endocrine dysfunction and its effects on tissue development and growth.     

Metabolism and pharmacokinetics of p-(3,3-dimethyl-1-triazeno) benzoic acid in M5076 sarcoma-bearing mice

Summary The pharmacokinetics of the anticancer agent p-(3,3-dimethyl-1-triazeno) benzoic acid (pCOOH-DMT), a drug now in phase I clinical trial in Europe, was investigated in C57 Bl female mice with M5076 reticulum-cell sarcoma that were treated i.v. with 200 mg/kg pCOOH-DMT. The drug disappeared from plasma with a terminal half-life of about 2.5 h. Plasma clearance was approximately 6 ml/min per kg. Distribution studies showed some differences in drug levels in different tissues. The highest levels were found in the tumor, liver, kidney and lung; lower levels were found in the spleen and gut, and the lowest, in the brain. The N-desmethyl derivative of pCOOH-DMT was not detectable in plasma or tissues of mice treated with the drug. Therefore, the previous evidence of low N-demethylation of pCOOH-DMT was confirmed. pCOOH-DMT glucuronide was identified by mass spectrometry and quantified by high-performance liquid chromatography (HPLC) in plasma, tissues and urine samples. pCOOH-DMT glucuronide appears to be the major urinary metabolite of pCOOH-DMT in mice. Another metabolite identified by mass spectrometry and quantified by HPLC in some tissues and urine was pCOOH-DMT glycinate.Abbreviations DTIlC 5-(3,3-dimethyl-l-triazeno)imidazole-4-carboxamide - pCOOH-DMT p-(3,3-dimethyl-l-triazeno)benzoic acid - pCOOH-MMT p-(3-methyl-l-triazeno)benzoic acid - pCONH₂-DMT p-(3,3-dimethyl-l-triazeno)carboxamide - BSTFA N,O-bis(trimethylsilyl)trifluoroacetamide - TMCS trimethylchlorosilane - TLC thin-layer chromatography - FAB fast atom bombardment - EI electron impact - M5 M5076 reticulum-cell sarcoma - t_1/2 beta-half-life - C₀ concentration time 0 - AUC area under the concentration vs time curve - Cl total clearance - V volume of distribution     

Exploring and embracing complexity in a distance-learning curriculum for physicians.

The recent pressures on clinical medicine such as the attention to medical error and the challenges of interdisciplinary care have also exerted pressure on health professions education. Educators must now gauge how to redesign education systems to adapt quickly to these disruptions. Sometimes disruptions can be self-inflicted, such as the VA National Quality Scholars Fellowship's decision to use interactive video (IV) as its primary medium for delivering the curriculum to its six sites around the nation. The authors describe how this disruption to their education system helped to fashion a learning environment that is adaptable. Along the journey from a classroom-based curriculum to an IV-based curriculum, the authors and others involved in the program learned the basic tenets of IV sessions, redefined the roles of the teachers and learners, and discovered an IV environment that functions as a complex adaptive learning system. This distance-learning curriculum can be a model for other health professions education, since it starts with simple rules, changes from within, has a tolerance for unpredictability, and continually moves forward and transforms itself despite tension.     

Scaffold protein harmonin (USH1C) provides molecular links between Usher syndrome type 1 and type 2

Usher syndrome (USH) is the most frequent cause of combined deaf-blindness in man. USH is clinically and genetically heterogeneous with at least 11 chromosomal loci assigned to the three USH types (USH1A-G, USH2A-C, USH3A). Although the different USH types exhibit almost the same phenotype in human, the identified USH genes encode for proteins which belong to very different protein classes and families. We and others recently reported that the scaffold protein harmonin (USH1C-gene product) integrates all identified USH1 molecules in a USH1-protein network. Here, we investigated the relationship between the USH2 molecules and this USH1-protein network. We show a molecular interaction between the scaffold protein harmonin (USH1C) and the USH2A protein, VLGR1 (USH2C) and the candidate for USH2B, NBC3. We pinpoint these interactions to interactions between the PDZ1 domain of harmonin and the PDZ-binding motifs at the C-termini of the USH2 proteins and NBC3. We demonstrate that USH2A, VLGR1 and NBC3 are co-expressed with the USH1-protein harmonin in the synaptic terminals of both retinal photoreceptors and inner ear hair cells. In hair cells, these USH proteins are also localized in the signal uptaking stereocilia. Our data indicate that the USH2 proteins and NBC3 are further partners in the supramolecular USH-protein network in the retina and inner ear which shed new light on the function of USH2 proteins and the entire USH-protein network. These findings provide first evidence for a molecular linkage between the pathophysiology in USH1 and USH2. The organization of USH molecules in a mutual 'interactome' related to the disease can explain the common phenotype in USH.