Microbubble Mediated Thrombus Dissolution with Diagnostic Ultrasound for the Treatment of Chronic Venous Thrombi

Background

Central venous catheter (CVC) thrombi result in significant morbidity in children, and currently available treatments are associated with significant risk. We sought to investigate the therapeutic efficacy of microbubble (MB) enhanced sonothrombolysis for aged CVC associated thrombi in vivo.

Methods and Results

A model of chronic indwelling CVC in the low superior vena cava with thrombus in situ was established after feasibility and safety testing in 7 pigs; and subsequently applied for repeated, sonothrombolytic treatments in 9 pigs (total 24 treatments). Baseline intracardiac echocardiography (ICE, 10.5F, Siemens), fluoroscopy and saline flushing confirmed the absence of any pre-existing CVC thrombus. A thrombus was then allowed to form and age over 24 hours. The created thrombus was localized and measured by ICE, and transthoracic image guided high mechanical index (MI) two-dimensional US treatments (1.1–1.7 MI; iE33, Philips) applied intermittently whenever intravenously infused MBs (3% MRX-801; NuVox) were visualized near the thrombus (n = 10; Group A). Control pigs (n = 10; Group B) received US without MB. All treatments were randomized. Post-treatment thrombus area by ICE planimetry was compared with pre-treatment measurements. Thrombus area measurements before and after treatment were 0.22 and 0.10 cm² respectively in Group A; compared to 0.24 and 0.21 cm² in Group B (p  = 0.0003). Effectiveness of longer duration US and MB thrombolytic treatments were studied (n = 4), which suggested that near complete thrombus dissolution is possible. No pulmonary emboli, alterations in oxygen saturation, or hemodynamics occurred with either treatment.

Conclusions

Guided high MI diagnostic US+systemic MB facilitates reduction of aged CVC associated thrombi in vivo. MB enhanced sonothrombolytic therapy may be a non-invasive safe alternative to thrombolytic agents in treating thrombotic CVC occlusions.     

Time‐shifted reproductive behaviours among fall armyworm (Noctuidae: Spodoptera frugiperda) host strains: evidence for differing modes of inheritance

The noctuid moth Spodoptera frugiperda consists of two strains associated with different larval host plants (most notably corn and rice). These strains exhibit differential temporal patterns of female calling and copulation during scotophase, with the corn strain more active earlier in the night. We investigated strain‐specific constraints in reproductive timing, mating interactions between the two strains, and the mode of inheritance of timing of female calling, male calling, copulation and oviposition. We observed an allochronic shift of all reproductive behaviours by approximately 3 h and a parallel shift of nonreproductive locomotor activity, suggesting involvement of the circadian clock. The corn strain was more variable in the timing of calling and copulation than the rice strain. Rice strain females were more restricted in the timing of copulation than rice strain males, while such differences between the sexes were not apparent in the corn strain. There were significant interactions between the strains affecting onset times of copulation and male calling. The four investigated reproductive traits differed in their modes of inheritance: timing of female and male calling exhibited strong maternal effects, timing of copulation was controlled by a combination of maternal effects and corn strain dominant autosomal factors, and timing of oviposition was inherited in a corn strain dominant fashion. We conclude that the allochronic separation of reproduction between fall armyworm strains is asymmetric, less pronounced than previously thought, and under complex genetic control.     

Mental patients in prisons

Mental conditions usually affect cognitive, emotional and volitional aspects and functions of the personality, which are also functions of interest in law, as they are essential at the time of adjudicating guilt, labeling the accused a criminal, and proffering a sentence. A relationship between mental illness and criminality has, thus, been described and given as one of the reasons for the large number of mental patients in prisons. Whether this relationship is one of causality or one that flows through many other variables is a matter of debate, but there is no debating that prisons have become a de facto part, and an important one, of mental health systems in many countries. This paper deals with the issue of the relationship and provides estimates of prevalence of mental patients in prisons culled from many studies in different countries. It also provides some direction for the management of mental patients as they crowd correctional systems.     

The genetic toxicology of ortho-toluidine.

ortho-Toluidine, a monosubstituted aniline and an intermediate in the dyeing industry, with a number of uses in other fields such as rubber processing and pharmaceutical production, has been in production for over 100 years. It is metabolised in vivo into a number of compounds, some of which are active genotoxins. It has been demonstrated to be a carcinogen in mice and rats and is a suspected human carcinogen. o-Toluidine has a wide range of genetic effects. It is a weak bacterial, fungal and mammalian mutagen, although the conditions required are stringent. The metabolising system used is of particular importance. o-Toluidine is also a clastogen, generally on prolonged exposure. It induces aneuploidy in both fungi and mammalian cultured cells. It also produces DNA damage (single-strand breaks and unscheduled DNA synthesis, UDS) and causes cell transformation. o-Toluidine can be considered a general genotoxin demonstrable under special conditions, particularly with regard to metabolism.     

Zebrafish promoter microarrays identify actively transcribed embryonic genes

We have designed a zebrafish genomic microarray to identify DNA-protein interactions in the proximal promoter regions of over 11,000 zebrafish genes. Using these microarrays, together with chromatin immunoprecipitation with an antibody directed against tri-methylated lysine 4 of Histone H3, we demonstrate the feasibility of this method in zebrafish. This approach will allow investigators to determine the genomic binding locations of DNA interacting proteins during development and expedite the assembly of the genetic networks that regulate embryogenesis.     

A tetravalent dengue nanoparticle stimulates antibody production in mice

Background

Dengue is a major public health problem worldwide, especially in the tropical and subtropical regions of the world. Infection with a single Dengue virus (DENV) serotype causes a mild, self-limiting febrile illness called dengue fever. However, a subset of patients experiencing secondary infection with a different serotype progresses to the severe form of the disease, dengue hemorrhagic fever/dengue shock syndrome. Currently, there are no licensed vaccines or antiviral drugs to prevent or treat dengue infections. Biodegradable nanoparticles coated with proteins represent a promising method for in vivo delivery of vaccines.

Findings

Here, we used a murine model to evaluate the IgG production after administration of inactivated DENV corresponding to all four serotypes adsorbed to bovine serum albumin nanoparticles. This formulation induced a production of anti-DENV IgG antibodies (p < 0.001). However, plaque reduction neutralization assays with the four DENV serotypes revealed that these antibodies have no neutralizing activity in the dilutions tested.

Conclusions

Our results show that while the nanoparticle system induces humoral responses against DENV, further investigation with different DENV antigens will be required to improve immunogenicity, epitope specicity, and functional activity to make this platform a viable option for DENV vaccines.