Ultrasound-mediated disruption of the blood tumor barrier for improved therapeutic delivery.

The blood-brain barrier (BBB) is a major anatomical and physiological barrier limiting the passage of drugs into brain. Central nervous system tumors can impair the BBB by changing the tumor microenvironment leading to the formation of a leaky barrier, known as the blood-tumor barrier (BTB). Despite the change in integrity, the BTB remains effective in preventing delivery of chemotherapy into brain tumors. Focused ultrasound is a unique noninvasive technique that can transiently disrupt the BBB and increase accumulation of drugs within targeted areas of the brain. Herein, we summarize the current understanding of different types of targeted ultrasound mediated BBB/BTB disruption techniques. We also discuss influence of the tumor microenvironment on BBB opening, as well as the role of immunological response following disruption. Lastly, we highlight the gaps between evaluation of the parameters governing opening of the BBB/BTB. A deeper understanding of physical opening of the BBB/BTB and the biological effects following disruption can potentially enhance treatment strategies for patients with brain tumors.

Palpable cardiac impulse predicts adequate acoustic windows.

In this study, we sought to determine the usefulness of palpating an apical cardiac impulse on physical examination in predicting adequate echocardiographic images for stress echocardiography. A variety of stress tests using either echocardiographic imaging or nuclear imaging are available to referring physicians. Deciding which test is best for a given patient is often difficult. In the case of stress echocardiography, the most significant limitation is poor image quality in a small portion of patients. We enrolled 136 consecutive outpatients referred for echocardiography. The presence or absence of a palpable cardiac apex on physical examination was recorded by two independent and blinded examiners. Data, including age, sex, weight, prior chest surgery, and smoking, were also collected. Echocardiographic imaging of the left ventricle was scored according to the number of adequately visualized wall segments in a standard 16-segment model. One hundred eleven patients (82%) had adequate visualization of at least 14 of 16 wall segments. Ninety-eight patients (72%) had a palpable cardiac impulse, of whom 90 (92%) also had adequate acoustic image quality versus only 21 (55%) of the 38 patients in whom an apex was not palpable (P<0.0001). Other variables that were measured were not significantly related to image quality, with the exception of weight; patients with adequate images weighed a mean of 75 kg versus 91 kg in those with inadequate images (P<0.0006). However, multivariate analysis showed a palpable apex to be the only independent predictor after controlling for other variables. A physical examination assessment for a palpable apical impulse is useful to predict adequate echocardiographic image quality for stress echocardiography. When used in conjunction with other parameters, this may lead to more appropriate referral to augmented stress testing.

Advanced heart block as a manifestation of a paraneoplastic syndrome from malignant thymoma.

Malignant thymoma is a rare tumor that is associated with paraneoplastic syndrome. Myocarditis as a paraneoplastic syndrome has been rarely described. Reported herein is a young male patient with malignant thymoma and myocarditis as part of a paraneoplastic syndrome. This resulted in high-degree heart block and an asystolic cardiac arrest despite placement of a permanent pacemaker.

Controlling isolated systolic hypertension. No time to be complacent.

Isolated systolic hypertension (ISH) is the most common form of hypertension in the elderly. It is an even better predictor of morbidity and mortality than is diastolic blood pressure. Several large trials have documented a clear benefit to treating ISH. Therapy should be initiated only after careful evaluation of the patient's overall medical status, because the elderly are at increased risk of adverse effects from medications. Pharmacologic therapy should be started at a low dose and increased slowly, if necessary. If hypertension is still present after the addition of two or three medications, a cause other than essential hypertension should be considered, such as white coat hypertension, secondary hypertension, or pseudohypertension.

Calcified right atrial mass in a woman receiving long-term intravenous phosphate therapy.

Right atrial masses are easily seen by 2-dimensional echocardiography and may represent primary tumors, secondary tumor invasion of the right atrium, tricuspid valve vegetations, or atrial thrombi. Calcification of right atrial masses is uncommon but easily identified by 2-dimensional echocardiography because of the high echogenicity of calcium deposits. We describe a patient with a heavily calcified right atrial thrombus caused by an indwelling central venous catheter and long-term intravenous phosphate infusion.

Developmental protein synthesis is required for the transcription of Dictyostelium prespore genes.

It has been established previously that the maintenance of expression of prespore-specific genes of Dictyostelium discoideum is prevented by the translational inhibitor cycloheximide. The drug had no effect upon the level of transcripts of the other genes examined, prestalk-specific or cell type-nonspecific. However, the interpretation of this result is open to question, because of possible nonspecific effects of cycloheximide. We have now characterized the cellular specificity and temporal profiles of mRNA accumulation of additional Dictyostelium cDNA clones, and have examined other inhibitors of in vivo protein synthesis. Four structurally and mechanistically distinct translational inhibitors each prevented the reaccumulation of prespore transcripts in cyclic AMP-primed, disaggregated amoebae. These results establish the importance of developmental protein synthesis in the accumulation of prespore gene transcripts. Nuclear run-on transcription assays were used to learn whether protein synthesis is required primarily for mRNA synthesis or transcript stability. A transcriptional time course first demonstrated that the abundance of these cell-specific transcripts during development mirrors their rates of synthesis. Significantly, the protein synthesis requirement of the prespore genes examined also occurs at the level of mRNA transcription, implying the existence of one or more developmentally regulated transcriptional activators.

Prespore gene expression in Dictyostelium requires concomitant protein synthesis.

It has been established previously that the maintenance of expression of prespore-specific genes of Dictyostelium discoideum is prevented by the translational inhibitor cycloheximide. The drug had no effect upon the level of transcripts of the other genes examined, prestalk-specific or cell type non-specific (Mehdy, M., Ratner, D. and Firtel, R., (1983) Cell 32, 763-771). We have now characterized the cellular specificity and temporal profiles of mRNA accumulation of additional Dictyostelium cDNA clones. Other inhibitors of in vivo protein synthesis have been examined, with emetine shown to be a particularly effective but reversible agent. Four structurally and mechanistically distinct translational inhibitors each prevented the reaccumulation of prespore transcripts in cyclic AMP-primed disaggregated amoebae. These results establish a role for protein synthesis in the transcription or transcript stability of prespore genes.