A connectivity mapping approach predicted acetylsalicylic acid (aspirin) to induce osteo/odontogenic differentiation of dental pulp cells.

AIM: To use connectivity mapping, a bioinformatics approach, to identify compounds that could induce odontogenic differentiation of dental pulp cells (DPCs) and to experimentally validate this effect. A subsidiary aim was to investigate the anti-inflammatory effect of any identified compound. METHODOLOGY: The Gene Expression Omnibus (GEO) database was searched for microarray data sets assessing odontogenic differentiation of human DPCs. An odontogenic gene expression signature was generated by differential expression analysis. The statistical significant connectivity map (ssCMap) method was used to identify compounds with a highly correlating gene expression pattern. DPCs were treated with the compound identified, and osteo/odontogenic differentiation was assessed by Alizarin red staining, alkaline phosphatase activity and expression of osteo/odontogenic genes ALPL, RUNX2, COL1A1, DSPP, DMP1 and SPP1 by RT-PCR. The anti-inflammatory effect of the compound was assessed using an ex vivo pulpitis model, and cytokine levels were measured with multiplex assay. Means were compared using the t-test or ANOVA followed by a Bonferroni post hoc test with the level of significance set at P ≤ 0.05. RESULTS: The GEO database search identified a specific gene expression signature for osteo/odontogenic differentiation. Analysis using ssCMap found that acetylsalicylic acid [(ASA)/aspirin] was the drug with the strongest correlation with that gene signature. The treatment of DPCs with 0.05 mmol L-1 ASA showed increased alkaline phosphatase activity (P < 0.001), mineralization (P < 0.05), and increased the expression of the osteo/odontogenic genes, DMP1 and DSPP (P < 0.05). Low concentration (0.05 mmol L-1 ) ASA reduced inflammatory cytokines IL-6 (P < 0.001), CCL21 (P < 0.05) and MMP-9 (P < 0.05) in an ex vivo pulpitis model. CONCLUSIONS: Connectivity mapping, a web-based informatics method, was successfully used to identify aspirin as a candidate drug that could modulate the differentiation of DPCs. Aspirin was shown to induce odontogenic differentiation in DPCs in vitro and this, together with its anti-inflammatory effects, makes it a potential candidate for vital pulp therapies.

Phenotype-driven molecular autopsy for sudden cardiac death.

A phenotype-driven approach to molecular autopsy based in a multidisciplinary team comprising clinical and laboratory genetics, forensic medicine and cardiology is described. Over a 13 year period, molecular autopsy was undertaken in 96 sudden cardiac death cases. A total of 46 cases aged 1-40 years had normal hearts and suspected arrhythmic death. Seven (15%) had likely pathogenic variants in ion channelopathy genes [KCNQ1 (1), KCNH2 (4), SCN5A (1), RyR2(1)]. Fifty cases aged between 2 and 67 had a cardiomyopathy. Twenty-five had arrhythmogenic right ventricular cardiomyopathy (ARVC), 10 dilated cardiomyopathy (DCM) and 15 hypertrophic cardiomyopathy (HCM). Likely pathogenic variants were found in three ARVC cases (12%) in PKP2, DSC2 or DSP, two DCM cases (20%) in MYH7, and four HCM cases (27%) in MYBPC3 (3) or MYH7 (1). Uptake of cascade screening in relatives was higher when a molecular diagnosis was made at autopsy. In three families, variants previously published as pathogenic were detected, but clinical investigation revealed no abnormalities in carrier relatives. With a conservative approach to defining pathogenicity of sequence variants incorporating family phenotype information and population genomic data, a molecular diagnosis was made in 15% of sudden arrhythmic deaths and 18% of cardiomyopathy deaths.

Particle-sounding of the spatial structure of kinetic Alfvén waves.

Kinetic Alfvén waves (KAWs) are ubiquitous throughout the plasma universe. Although they are broadly believed to provide a potential approach for energy exchange between electromagnetic fields and plasma particles, neither the detail nor the efficiency of the interactions has been well-determined yet. The primary difficulty has been the paucity of knowledge of KAWs' spatial structure in observation. Here, we apply a particle-sounding technique to Magnetospheric Multiscale mission data to quantitatively determine the perpendicular wavelength of KAWs from ion gyrophase-distribution observations. Our results show that KAWs' perpendicular wavelength is statistically 2.4[Formula: see text] times proton thermal gyro-radius. This observation yields an upper bound of the energy the majority proton population can reach in coherent interactions with KAWs, that is, roughly 5.76 times proton perpendicular thermal energy. Therefore, the method and results shown here provide a basis for unraveling the effects of KAWs in dissipating energy and accelerating particles in a number of astrophysical systems, e.g., planetary magnetosphere, astrophysical shocks, stellar corona and wind, and the interstellar medium.

Observational evidence of ring current in the magnetosphere of Mercury.

The magnetic gradient and curvature drift of energetic ions can form a longitudinal electric current around a planet known as the ring current, that has been observed in the intrinsic magnetospheres of Earth, Jupiter, and Saturn. However, there is still a lack of observational evidence of ring current in Mercury's magnetosphere, which has a significantly weaker dipole magnetic field. Under such conditions, charged particles are thought to be efficiently lost through magnetopause shadowing and/or directly impact the planetary surface. Here, we present the observational evidence of Mercury's ring current by analysing particle measurements from MErcury Surface, Space Environment, GEochemistry, and Ranging (MESSENGER) spacecraft. The ring current is bifurcated because of the dayside off-equatorial magnetic minima. Test-particle simulation with Mercury's dynamic magnetospheric magnetic field model (KT17 model) validates this morphology. The ring current energy exceeds [Formula: see text] J during active times, indicating that magnetic storms may also occur on Mercury.

Simultaneous macroscale and microscale wave-ion interaction in near-earth space plasmas.

Identifying how energy transfer proceeds from macroscales down to microscales in collisionless plasmas is at the forefront of astrophysics and space physics. It provides information on the evolution of involved plasma systems and the generation of high-energy particles in the universe. Here we report two cross-scale energy-transfer events observed by NASA's Magnetospheric Multiscale spacecraft in Earth's magnetosphere. In these events, hot ions simultaneously undergo interactions with macroscale (~[Formula: see text] km) ultra-low-frequency waves and microscale ([Formula: see text] km) electromagnetic-ion-cyclotron (EMIC) waves. The cross-scale interactions cause energy to directly transfer from macroscales to microscales, and finally dissipate at microscales via EMIC-wave-induced ion energization. The direct measurements of the energy transfer rate in the second event confirm the efficiency of this cross-scale transfer process, whose timescale is estimated to be roughly ten EMIC-wave periods about (1 min). Therefore, these observations experimentally demonstrate that simultaneous macroscale and microscale wave-ion interactions provide an efficient mechanism for cross-scale energy transfer and plasma energization in astrophysical and space plasmas.

MMS observations of electron scale magnetic cavity embedded in proton scale magnetic cavity.

Magnetic cavities (sometimes referred to as magnetic holes) at electron kinetic scale are thought to be one of the extremely small intermittent structures formed in magnetized turbulent plasmas, where the turbulence energy cascaded down to electron scale may finally be dissipated and consequently energize the electrons. However, the geometry and formation of these structures remain not definitively resolved. Here we discuss an electron scale magnetic cavity embedded in a proton scale magnetic cavity observed by the MMS spacecraft in the magnetosheath. By applying an innovative particle sounding technique, we directly depict the boundary of the electron scale magnetic cavity and uncover the geometry. We find that this structure is nearly circular with a radius of 10.0 km and its formation is due to the diamagnetic current. Investigation of the electron scale structure is only recently made possible by the high spatial and temporal resolution provided by MMS observations.

Recent advances in the use of DNA vaccines for the treatment of diseases of farmed animals.

DNA-based vaccination constitutes one of the most recent approaches to vaccine development. This technology is in principle one of the most simple and yet versatile methods of inducing both humoral and cellular immune responses, as well as protection against a variety of infectious agents. However, although immune responses have been induced in a number of larger species, most information on the efficacy of DNA immunization has been generated in mice. In this review the information available to date about the use of DNA vaccines in farmed animals, including cattle, pigs and poultry, is presented. The areas that need specific attention in the future to bring this technology to the market are discussed, including the issues concerning delivery, safety, compatibility of plasmids in multivalent vaccines and the potential of using immune stimulants as part of a DNA vaccine.

Administrative relationships between state hospitals and academic psychiatry departments.

To review administrative relationships between academic departments of psychiatry and state hospitals the authors sent a questionnaire survey to chairmen of the 115 psychiatry departments in the United States with approved residency programs, receiving responses from 98 (85%). They discuss three types of relationships and examine the nature of the training of university residents in state hospitals, providing suggestions for integrating service-oriented settings such as state hospitals into an academic psychiatry program.

The VA psychiatry service as a setting for residency education.

The authors report data from a survey of chairmen of academic departments of psychiatry and chiefs of Veterans Administration (VA) psychiatry services concerning administrative relationships between academic psychiatry departments and VA psychiatry services and the education of psychiatry residents in VA settings. The extent and quality of relationships, the interdependence of academic departments and VA psychiatry services, factors important for good VA training, and advantages and disadvantages of using the VA for residency education are documented. The authors present their conclusions and recommendations for improving the quality of relationships between academic departments and VA psychiatry services and for strengthening psychiatric education in the VA setting.

A visual assay to monitor purification of cell surface antigens reacting with monoclonal antibodies.

We have developed a visual microtiter assay to detect solubilized cell-surface antigens which react with monoclonal antibodies. The assay depends on the ability of adsorbed monoclonal antibody to bind target cells to microtiter V wells, and the inhibition of binding by antigen. We have used this assay to follow a 600-fold purification of the human lymphocyte differentiation antigen 3A1 extracted from HSB-2 cells. Antigen 3A1 is a glycoprotein with a molecular weight of approximately 40,000 daltons.

Loeffler's endocarditis presenting as mitral and tricuspid stenosis.

Loeffler's endocarditis characteristically produces cardiac dysfunction by the combined effects of endocardial fibrosis with restriction to diastolic inflow and intracavitary thrombosis with partial cavity obiliteration. Although valve dysfunction may complicate this condition, it is rarely of primary hemodynamic significance. This report describes an unusual case in which mitral and tricuspid stenosis were the primary cardiac lesions. Because of the critical nature of the valve stenosis, surgical intervention was attempted despite evidence of left ventricular involvement. This case suggests than when significant valve dysfunction complicates Loeffler's endocarditis, surgical revision may be undertaken with at least temporary amelioration of the valve disorder and without apparent adverse effect on the underlying disease process.

Renal insufficiency is a component of COACH syndrome.

Two sisters, ages 23 years and 6 years, respectively, were found to have congenital ataxia, bilateral coloboma, mental retardation and abnormal liver function. Magnetic resonance imaging showed cerebellar vermis hypoplasia in the younger girl and liver biopsy showed hepatic fibrosis in the older sister. This combination of findings suggested a diagnosis of COACH syndrome which is characterized by hypoplasia of cerebellar vermis, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis. COACH syndrome is a newly recognized condition. So far, five cases have been reported from three sibships. We report two additional cases from one sibship and suggest that several other cases may already exist in literature that were not recognized as having COACH syndrome. The occurrence of multiple cases in single sibships suggests autosomal recessive inheritance. In addition to previously described findings typical of COACH syndrome, the older of our patients showed progressive renal insufficiency with fibrocystic changes on renal biopsy. Renal function has not been described consistently in previous reports of COACH syndrome but has been abnormal in all cases in which it has been investigated. We suggest that renal insufficiency should be considered a common manifestation of COACH syndrome.

Iohexol vs. diatrizoate. A comparative study in intravenous urography.

A randomized double-blind study comparing the use of iohexol with diatrizoate in intravenous urography was performed in 435 patients in nine centers. Contrast media were evaluated for safety, incidence of adverse side effects, and efficacy. Multiple hematologic and biochemical parameters were observed, as well as blood pressure and pulse, at intervals before and after injection. Severity, nature, and duration of side effects were recorded together with the attending physician's clinical assessment. Coned radiographs of the kidneys were done immediately after injection and were repeated at 1-, 5-, 10-, and 20-minute intervals. Films were evaluated for quality of image. A significantly higher number of excellent studies were obtained with iohexol than with diatrizoate. Remarkably few side effects and adverse reactions reported for iohexol establish the safety and suitability of this nonionic contrast medium for intravenous urography.

Stability studies on chemoembolization mixtures. Dialysis studies of doxorubicin and lipiodol with Avitene, Gelfoam, and Angiostat.

RATIONALE AND OBJECTIVES: Chemoembolization, using a combination of embolic and chemotherapeutic agents, appears to be an effective treatment for hepatocellular carcinoma. Although the postulated mechanism of effectiveness hinges on a prolonged drug delivery, increasing evidence suggests that embolization mixtures are not stable. The objective of this study was to investigate examples of these mixtures. METHODS: Dialysis techniques have been used to examine the pharmacokinetic properties of chemoembolization mixtures that contain doxorubicin, Lipiodol (Guerbet Products, Montreal, Quebec), and the embolizing agents Avitene (Alcon Laboratories Inc., Fort Worth, Texas), Gelfoam (Upjohn, Kalamazoo, MI), and Angiostat (Regional Therapeutic Inc., Pacific Palisades, CA). RESULTS: Lipiodol, Gelfoam, and Avitene, when combined with doxorubicin, had only a small effect on the diffusion of the drug when compared with the diffusion curve of doxorubicin alone. Gelfoam or Avitene produced a thrombus-like consistency when added to a doxorubicin/Lipiodol combination, and an additional decrease in the doxorubicin appearance rate was observed. However, after 6 hours, doxorubicin levels for these mixtures reached control values observed in 3 hours. Angiostat without Lipiodol produced a profound concentration-dependent decrease in the diffusion of doxorubicin. After 9 hours, only 23% of the doxorubicin had been released. CONCLUSION: The strong complexing ability of the embolic agent Angiostat may enable it to be a carrier for doxorubicin and surpass other mixtures currently employed for transcatheter chemoembolization.

Detachable balloon occlusion of bronchopleural fistulae in dogs.

The use of detachable balloon occlusion in closure of bronchopleural fistulae was investigated in eight dogs. Fistula occlusion could not be achieved in one dog, and the balloon was not large enough to occlude a fistula in a second dog. Satisfactory fistula occlusion was achieved in the remaining six dogs. All fistulae occluded were shown to be satisfactorily healed at ten days. There were no significant sequelae to bronchial occlusion during this period. Detachable balloon occlusion of bronchopleural fistulae has the potential for satisfactory fistula control prior to more definitive surgery.

Problems in assessment of pulmonary parenchymal consolidation in heart transplant candidates.

Radiologic assessment of the cause of pulmonary parenchymal consolidation in end-stage heart failure may be difficult. From August 1982 to May 1989, 22 patients being considered for orthotopic cardiac allografts had parenchymal consolidation on their chest radiographs, most commonly in the right lower lobe. Our purpose was to determine from standard radiologic studies whether this consolidation represented alveolar pulmonary edema in an atypical basal distribution, pneumonia, or pulmonary infarction. This differentiation is important because pneumonia is an absolute and infarction is a relative contraindication to surgery, whereas successful transplantation can be performed in a setting of pulmonary edema. The chest radiographs were reviewed retrospectively. When available, pulmonary angiograms, nuclear medicine ventilation/perfusion scans, and needle biopsy findings were also evaluated. The radiologic assessment was correlated with the results of surgical, autopsy, or clinical outcome. None of the conventional modalities was very accurate--the plain chest film was correct in only 63%, nuclear medicine studies in 50%. Angiography was the single most useful test, with an accuracy of 75%.

Management of superior gluteal artery aneurysm by percutaneous balloon catheter occlusion: a case report.

A 19-year-old woman developed an aneurysm of the left superior gluteal artery following laparoscopy. Percutaneous insertion of a balloon catheter into the neck of the aneurysm for 48 hours resulted in permanent thrombosis of the aneurysm. Use of balloon catheters in the management of surgically inaccessible vascular lesions in discussed.

Pseudotumor of kidney.

Pyelocancerous backflow during retrograde pyelography is a roentgen sign indicating renal tumors. An example of a pseudotumor (renal hematoma caused by anticoagulation) is presented which displayed this type of backlfow, demonstrating the nonspecificity of the sign. The diagnostic, especially radiographic, findings of intrarenal hematoma are discussed.

Duplex and color Doppler flow sonography of occlusion and near occlusion of the carotid artery.

PURPOSE: To determine whether color Doppler flow imaging with the use of slow-flow sensitivity improves sensitivity and specificity in the differentiation of occlusion and near occlusion of the internal carotid artery. METHODS: Color Doppler and duplex sonography were performed in symptomatic patients who had angiographically confirmed occlusion and/or near occlusion of the internal carotid artery. The study consisted of two phases: in the first, we assessed the usefulness of color Doppler flow imaging by retrospectively reviewing the records of 35 patients with 36 angiographically confirmed occlusions or near occlusions of the internal carotid artery who were examined with color Doppler flow imaging at our institution during a period of 4 years; in the second phase, we incorporated color Doppler sonography into the routine scanning protocols of 39 patients with 41 occluded or nearly occluded internal carotid arteries seen over a period of 2 1/2 years. RESULTS: Overall, color Doppler imaging correctly showed all 34 of the near occlusions (sensitivity, 100%) and 36 of the 43 occlusions (specificity, 84%). Seven patients with angiographically confirmed occlusion had sonographic findings that suggested near occlusion. In the first phase, eight near occlusions were misinterpreted as occlusions with conventional duplex sonography, but were correctly shown with color Doppler flow imaging. In the second phase, sensitivity increased from 50% to 100% (18 or 18) because of better detection of the nearly occluded lumen. This was at the expense of a decrease in specificity (from 100% to 78%). owing to identification of apparent flow in the internal carotid artery on color Doppler flow images in five of 23 occlusions. CONCLUSION: Because of its ability to depict slow flow, color Doppler imaging with slow-flow sensitivity is superior to conventional duplex sonography for the noninvasive discrimination of occlusion from near occlusion of the internal carotid artery.

Percutaneous gastrojejunostomy in amyotrophic lateral sclerosis.

We have performed a retrospective review of the use of a percutaneous gastrojejunostomy in patients with amyotrophic lateral sclerosis (ALS). Forty-one patients with initial bulbar manifestations of ALS and 32 patients with initial limb manifestations underwent a percutaneous gastrojejunostomy under fluoroscopic control using the Rankin gastrojejunostomy tube. Survival characteristics were compared with 86 bulbar onsetting and 207 limb onsetting ALS patients who did not require nutritional support. The 30-day mortality rate was 9.6% (respiratory death in three bulbar onsetting patients and four limb onsetting patients) and the 30 day morbidity rate was 4.1% (one operative site infection and intraperitoneal leakage in two patients). The most frequent long-term complication was the requirement for tube changing (blockage in six; dislodgment in two). Gastric reflux was not described amongst the treated patients. Overall survivorship (symptom onset to death) was less in the bulbar onsetting patients receiving a gastrojejunostomy tube than in the control population (median survival 22.0 vs. 33.7 months, respectively, P=0.005). As a group, the median survivorship for limb onsetting patients was not different for those receiving a gastrojejunostomy than for those who did not. However, a significant reduction in survival was observed in limb onsetting patients receiving a gastrojejunostomy early in the course of their disease (P=0.001) compared to those with a longer duration prior to the procedure. This was not observed in the bulbar onsetting patients. In both patient populations, no relationship was observed between survival post-gastrojejunostomy and the severity of pulmonary involvement at the time of the intervention, serum chloride, or age at onset. These studies demonstrate that a percutaneous gastrojejunostomy is a well-tolerated and safe alternative technique for enteral nutritional support in ALS patients. It also offers the advantage of not requiring either a general anaesthetic at the time of the procedure or instrumentation through the oropharynx. We have also observed that limb onsetting patients requiring a gastrojejunostomy early in the course of their illness are in a distinctive, less favorable, prognostic group.