Further delineation of Kabuki syndrome in 48 well-defined new individuals

Kabuki syndrome is a multiple congenital anomaly/mental retardation syndrome. This study of Kabuki syndrome had two objectives. The first was to further describe the syndrome features. In order to do so, clinical geneticists were asked to submit cases-providing clinical photographs and completing a phenotype questionnaire for individuals in whom they felt the diagnosis of Kabuki syndrome was secure. All submitted cases were reviewed by four diagnosticians familiar with Kabuki syndrome. The diagnosis was agreed upon in 48 previously unpublished individuals. Our data on these 48 individuals show that Kabuki syndrome variably affects the development and function of many organ systems. The second objective of the study was to explore possible etiological clues found in our data and from review of the literature. We discuss advanced paternal age, cytogenetic abnormalities, and familial cases, and explore syndromes with potentially informative overlapping features. We find support for a genetic etiology, with a probable autosomal dominant mode of inheritance, and speculate that there is involvement of the interferon regulatory factor 6 (IRF6) gene pathway. Very recently, a microduplication of 8p has been described in multiple affected individuals, the proportion of individuals with the duplication is yet to be determined.     

Ultrasonic technique for imaging tissue vibrations: preliminary results

We propose an ultrasound (US)-based technique for imaging vibrations in the blood vessel walls and surrounding tissue caused by eddies produced during flow through narrowed or punctured arteries. Our approach is to utilize the clutter signal, normally suppressed in conventional color flow imaging, to detect and characterize local tissue vibrations. We demonstrate the feasibility of visualizing the origin and extent of vibrations relative to the underlying anatomy and blood flow in real-time and their quantitative assessment, including measurements of the amplitude, frequency and spatial distribution. We present two signal-processing algorithms, one based on phase decomposition and the other based on spectral estimation using eigen decomposition for isolating vibrations from clutter, blood flow and noise using an ensemble of US echoes. In simulation studies, the computationally efficient phase-decomposition method achieved 96% sensitivity and 98% specificity for vibration detection and was robust to broadband vibrations. Somewhat higher sensitivity (98%) and specificity (99%) could be achieved using the more computationally intensive eigen decomposition-based algorithm. Vibration amplitudes as low as 1 mum were measured accurately in phantom experiments. Real-time tissue vibration imaging at typical color-flow frame rates was implemented on a software-programmable US system. Vibrations were studied in vivo in a stenosed femoral bypass vein graft in a human subject and in a punctured femoral artery and incised spleen in an animal model.     

Molecular typing of West Nile Virus, Dengue, and St. Louis encephalitis using multiplex sequencing

We report the development of an assay to simultaneously identify three of the clinically important flaviviruses (West Nile Virus, Dengue, and St. Louis encephalitis). This assay is based on the nucleotide sequence variations within a 266-bp region of the non-structural protein 5. Further, based on the nucleotide variations in the same region of the non-structural protein 5, four of the present Dengue serotypes were identified. To identify some of the subtypes of WNV we have developed a second assay using multiplex sequencing technology. The format of the result of this assay is an electropherogram of two genomic segments of the WNV genome: a 48-nucleotide sequence from the anchored core protein C and a 45-nucleotide sequence coding for the non-structural proteins (proteinase and putative helicase genes).     

Prediction of complications following nonemergency percutaneous coronary interventions

Previous models for prediction of complications after percutaneous coronary interventions (PCIs) have included in-hospital mortality and major in-hospital complications. In general, these models have excluded elevated cardiac biomarkers as a complication. We sought to determine whether a risk model could predict complications, including biomarker elevation, in patients undergoing nonemergency PCI. We examined the outcomes of nonemergency PCI performed on patients at Mayo Clinic from 2000 to 2003. The primary end point was in-hospital complications of death, myocardial infarction (MI) (Q-wave MI, or post-PCI creatine kinase-MB elevation >or=3 times the upper limit of normal), emergency coronary artery bypass grafting, or stroke. We used the Hosmer-Lemeshow test to demonstrate the adequacy of the model fit, and the c-index for discriminatory ability of the model. Of 2,894 nonemergency PCIs, the end point was noted in 232 (8%). The final prediction model included vein graft intervention (odds ratio [OR] 2.19), angiographic thrombus (OR 2.12), preprocedure stenosis of a minor (OR 1.98) or major (OR 1.62) side branch, and type C lesion (OR 1.48). The model had modest ability to discriminate between event and nonevent patients (c = 0.641). In the 500 bootstrap samples for internal validation, the c-index was 0.642 +/- 0.020, indicating only fair discriminatory ability. The average number of observed events was 232.0 +/- 14.7 compared with 232.1 +/- 2.5 expected events (average difference -0.06 +/- 14.5). In conclusion, the 5 risk variables associated with an increased risk of complications in patients undergoing elective PCI included vein graft intervention, presence of angiographic thrombus, stenosis of a major or minor side branch, and type C lesion; however, the discriminatory ability of the model derived from the variables was only modest.     

Acanthamoeba keratitis during orthokeratology

PURPOSE: To report an infectious complication of overnight rigid gas-permeable contact lenses. METHODS: Case report and medical literature review. RESULTS: A 16-year-old girl developed laboratory-confirmed acanthamoebic keratitis during orthokeratology for myopic reduction. Recent case reports suggest that Acanthamoeba is a cause of microbial keratitis associated with gas-permeable contact lenses among teenagers and young adults undergoing orthokeratology. CONCLUSIONS: Acanthamoeba keratitis is an emerging complication of orthokeratology in young myopes.     

An integrated pharmacokinetic and pharmacodynamic study of arsenite action 2. Heme oxygenase induction in mice

Heme oxygenase (HO) is the rate-limiting enzyme in heme degradation and its activity has a significant impact on intracellular heme pools. Rat studies indicate that HO induction is a sensitive, dose-dependent response to arsenite (As(III)) exposure in both liver and kidney. The objective of this study was to evaluate the relationship of HO induction to administered As(III) dose, and concentrations of inorganic arsenic (iAs) in tissues and urine. Levels of iAs, mono- (MMA) and dimethylated arsenic (DMA) as well as HO activity were determined in liver, lung and kidney over time in female B6C3F1 mice given a single oral dose of 0, 1, 10, 30 or 100 micromol/kg As(III). Increased HO activity was a time and dose-dependent response in liver and kidney, but not in lung. Activity peaked in the 4-6 h time range in liver and kidney with the responsiveness in liver being approximately 2- to 3-fold greater than kidney. The lowest observed effect levels (LOELs) in this study for HO induction are 30 and 100 micromol/kg, respectively, in liver and kidney. The predominant form of arsenic (As) was iAs in liver at all doses, whereas DMA was the predominant form of As in kidney at all doses. Three- to four-fold higher levels of iAs were achieved in liver compared to kidney. MMA was the least abundant form of As in liver and kidney, never exceeding more than 20% of the total As present. The concentration of iAs in tissue or urine demonstrated the strongest correlation with HO activity in both liver and kidney. Results of this study suggest that HO induction is a biomarker of effect that is specific for tissue iAs because a high, but nontoxic, acute dose of DMA (5220 micromol/kg) did not induce HO in mice. Thus, HO induction has potential for use as a biomarker of effect for inorganic arsenic exposure and may be used as an indicator response to further the development of a biologically-based dose response model for As.     

Unaided smoking cessation among smokers in treatment for alcohol dependence

To investigate the possible impact of treatment of alcohol dependence on smoking, we studied 144 smokers in an alcohol treatment center for whom 6-month data were available. Of those, 18 reported not smoking at 6 months. No significant differences in age, gender, or race were observed between quitters and continuing smokers. Quitters at 6 months were significantly more likely to be low dependent smokers than were continuing smokers and were significantly more likely to report no drinking during the past 28 days at the end of 1 month's treatment (93%) than continuing smokers (62%). These findings suggest that quitting smoking may be associated with low levels of nicotine dependence and favorable alcohol treatment response in alcoholic smokers.     

6-Benzylthioinosine analogues as subversive substrate of Toxoplasma gondii adenosine kinase: activities and selective toxicities

Toxoplasma gondii adenosine kinase (EC.2.7.1.20) is the major route of adenosine metabolism in this parasite. The enzyme is significantly more active than any other enzyme of the purine salvage in T. gondii and has been established as a potential chemotherapeutic target for the treatment of toxoplasmosis. Certain 6-substituted purine nucleosides act as subversive substrates of T. gondii, but not the human, adenosine kinase. Therefore, these compounds are preferentially metabolized to their respective nucleotides and become selectively toxic against the parasites but not their host. Herein, we report the testing of newly synthesized 6-benzylthioinosine analogues with various substituents on the phenyl ring of their benzyl group as subversive substrates of T. gondii adenosine kinases. The binding affinity of these compounds to T. gondii adenosine kinase and their efficacy as antitoxoplasmic agents varied depending on the nature and position of the various substituents on the phenyl ring of their benzyl group. p-Cyano-6-benzylthioinosine and 2,4-dichloro-6-benzylthioinosine were the best ligands. In general, analogues with substitution at the para position of the phenyl ring were better ligands than those with the same substitutions at the meta or ortho position. The better binding of the para-substituted analogues is attributed to the combined effect of hydrophobic as well as van der Waals interactions. The 6-benzylthioinosine analogues were devoid of host-toxicity but all showed selective anti-toxoplasmic effect in cell culture and animal models. These results further confirm that toxoplasma adenosine kinase is an excellent target for chemotherapy and that 6-substituted purine nucleosides are potential selective antitoxoplasmic agents.     

Causes of death in HIV infection: the key determinant to define the clinical response to anti-HIV therapy

Studies have shown an increased risk of new AIDS/death among injecting drug users (IDU) starting highly active antiretroviral therapy (HAART). Of 3872 patients starting HAART in the EuroSIDA study, 819 were IDU (21.2%). During 14 769 person-years of follow-up, 499 patients progressed to new AIDS/death. Compared with homosexual individuals, IDU had an increased incidence of new AIDS/death, but only for non-HIV deaths. There is an urgent need to define and standardize causes of death in observational studies.     

Platelets deliver costimulatory signals to antigen-presenting cells: a potential bridge between injury and immune activation

The danger model of immunity and tolerance holds that antigen-presenting cells (APCs), activated by stress, injury, or necrosis, but not by physiological (apoptotic) cell death, initiate adaptive immune responses. APC activation is fundamentally associated with binding of CD40 to its ligand CD154. Platelets express CD154 upon activation and are thus potential primal danger signals linking the homeostatic response to trauma to activation of the acquired immune system. Previously, we showed that platelets can undergo gradient-driven migration, or chemotaxis, toward supernatants from cells injured by repeated freeze/thaws, UV light, or ischemia/reperfusion. Herein, we demonstrate that platelet-derived CD154 induces immature dendritic cell maturation with upregulation of costimulatory molecules and IL-12p40 production. Overall, these results provide a mechanism for platelet activation of APC facilitating the induction of adaptive immunity in environments of cell injury.