Congenital heart disease often features structural abnormalities that emerge during development. Accumulating evidence indicates a crucial role for cardiac contraction and the resulting fluid forces in shaping the heart, yet the molecular basis of this function is largely unknown. Using the zebrafish as a model of early heart development, we investigated the role of cardiac contraction in chamber maturation, focusing on the formation of muscular protrusions called trabeculae. By genetic and pharmacological ablation of cardiac contraction, we showed that cardiac contraction is required for trabeculation through its role in regulating notch1b transcription in the ventricular endocardium. We also showed that Notch1 activation induces expression of ephrin b2a (efnb2a) and neuregulin 1 (nrg1) in the endocardium to promote trabeculation and that forced Notch activation in the absence of cardiac contraction rescues efnb2a and nrg1 expression. Using in vitro and in vivo systems, we showed that primary cilia are important mediators of fluid flow to stimulate Notch expression. Together, our findings describe an essential role for cardiac contraction-responsive transcriptional changes in endocardial cells to regulate cardiac chamber maturation.

Significance: Forces are important in the cardiovascular system, acting as regulators of vascular physiology and pathology. Residing at the blood vessel interface, cells (endothelial cell, EC) are constantly exposed to vascular forces, including shear stress. Shear stress is the frictional force exerted by blood flow, and its patterns differ based on vessel geometry and type. These patterns range from uniform laminar flow to nonuniform disturbed flow. Although ECs sense and differentially respond to flow patterns unique to their microenvironment, the mechanisms underlying endothelial mechanosensing remain incompletely understood. Recent Advances: A large body of work suggests that ECs possess many mechanosensors that decorate their apical, junctional, and basal surfaces. These potential mechanosensors sense blood flow, translating physical force into biochemical signaling events. Critical Issues: Understanding the mechanisms by which proposed mechanosensors sense and respond to shear stress requires an integrative approach. It is also critical to understand the role of these mechanosensors not only during embryonic development but also in the different vascular beds in the adult. Possible cross talk and integration of mechanosensing via the various mechanosensors remain a challenge. Future Directions: Determination of the hierarchy of endothelial mechanosensors is critical for future work, as is determination of the extent to which mechanosensors work together to achieve force-dependent signaling. The role and primary sensors of shear stress during development also remain an open question. Finally, integrative approaches must be used to determine absolute mechanosensory function of potential mechanosensors. Antioxid. Redox Signal. 25, 373–388.

The increased hospital stay and excess hospitalization costs that resulted from Foley catheter-associated urinary tract infection after 5 common surgical procedures were evaluated in a case-matched and controlled study. Nosocomial urinary tract infections increased postoperative hospital stay by an average of 2.4 days (p equals 0.017) and increased hospital costs by $558 per patient. Recommendations for prevention of urinary catheter-associated infections can be assessed accurately by comparison to the parameters of morbidity and cost.

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\s=b\The treatment of 162 patients with squamous cell carcinoma of the tonsil seen at the University of Virginia Medical Center, Charlottesville, from 1955 through 1974 was reviewed. One hundred four patients form the basis of this report. The patients were grouped by the stage of disease, and then three-and five-year determinate survival, recurrences, distant metastases, and complications were examined. The treatment used was surgery, radiation, or a combination of preoperative radiation and surgery. The overallfive-year determinate survival for stage I was 93%; stage II, 57%; stage III, 27%; and stage IV, 17%. The five-year determinate survivals of patients treated with surgery alone, radiation, and combination therapy were 88%, 27%, and 32%, respectively. The latter two treatment modalities were biased by a greater proportion of patients with stage III and IV disease, whereas surgery alone included a high proportion of patients with stage I and II disease. Based on this review and those reported in the literature, we recommend radical radiation therapy for stage I and II disease and combination radiation therapy and composite resection for stages III and IV. (Arch Otolaryngol 1981;107:730-734) Squamous cell carcinoma of the ton¬ sil is second in frequency to carci¬ noma of the larynx among upper res-

Fibronectin (FN) assembly and fibrillogenesis are critically important in both development and the adult organism, but their importance in vascular functions is not fully understood. Here we identify a novel pathway by which haemodynamic forces regulate FN assembly and fibrillogenesis during vascular remodelling. Induction of disturbed shear stress in vivo and in vitro resulted in complex FN fibril assembly that was dependent on the mechanosensor PECAM. Loss of PECAM also inhibited the cell-intrinsic ability to remodel FN. Gain- and loss-of-function experiments revealed that PECAM-dependent RhoA activation is required for FN assembly. Furthermore, PECAM−/− mice exhibited reduced levels of active β1 integrin that were responsible for reduced RhoA activation and downstream FN assembly. These data identify a new pathway by which endothelial mechanotransduction regulates FN assembly and flow-mediated vascular remodelling.

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