Endothelial dysfunction is associated with multiple vascular diseases and lacks effective treatment options. Activated Protein C (aPC) is a promising biotherapeutic that signals via protease-activated receptor-1 (PAR1) to promote diverse cytoprotective responses, including endothelial barrier stabilization, anti-inflammatory, and anti-apoptotic activities, which require specific co-receptors. We show that aPC-activated PAR1 signals preferentially via β-arrestin-2 (β-arr2) and dishevelled-2 (Dvl-2) scaffolds rather than heterotrimeric G proteins. However, the mechanisms by which aPC/PAR1 elicits diverse cytoprotective responses are poorly defined. Here we define a novel β-arrestin-2-mediated sphingosine kinase-1 (SphK1)-sphingosine-1-phosphate receptor-1 (S1PR1)-Akt signaling axis that confers aPC/PAR1-mediated protection against cell death. aPC stimulates the phosphorylation, translocation, and activation of SphK1 and is dependent on β-arrestin-2 and not Dvl-2. Moreover, aPC/PAR1 markedly increases S1PR1-caveolin-1 co-association, although both receptors co-existed in caveolin-1 enriched microdomains before aPC stimulation. These studies reveal that aPC/PAR1 cytoprotective responses are mediated by discrete β-arr2-driven signaling pathways modulated by co-receptors localized in caveolae.

No abstract

No abstract

Haemothorax as the predominant clinical sign following acute strangulation of a diaphragmatic hernia is unusual enough to warrant record. CASE HISTORYThe patient, a farm labourer aged 37, gave a history of previous good health, although he had complained to his family of occasional indigestion. On Jan. 14, 1942, he felt severe abdominal pain immediately after supper. He was seen by one of us (S. M. S.), who found him shocked and restless, with temperature 970, pulse 100, and respirations 20. There was tenderness on deep palpation below the left costal margin but no rigidity. Dullness with diminished air entry was found at the left base, suggesting effusion. He was neither dyspnoeic nor cyanosed. He had been sick once, the vomit appearing normal.He was admitted to Evesham Hospital on Jan. 15, and at 11 a.m., because the physical signs indicated a rapid increase in the amount of fluid and his condition was deteriorating, an exploratory needle was introduced into the fifth space in the left mid-axillary line, and 10 c.cm. of normal-looking venous blood was withdrawn. A radiograph of the chest revealed that the heart and mediastinum were well over to the right, and there was a dense uniform opacity over the whole of the left lung field. When seen by another of us (S. D.) on the 16th the patient was orthopnoeic and had begun to vomit a little blood. The physical signs all pointed to the thorax: abdominal examination did not suggest anything abnormal there. 27 c.cm. of apparently normal venous blood was then removed from the chest. A second radiograph taken immediately after this showed that the heart and mediastinum were still over to the right; no fluid was now apparent on the left side, although there was diminished translucency. In the upper part of the left lung-field could be seen what appeared to be a loop of intestine, and irregular opacities were noted immediately above the left diaphragm. The left lung was collapsed against the mediastinum. At this stage the patient was seen by Dr. Haslett of Cheltenham, who diagnosed a ruptured diaphragmatic hernia. The patient's general condition deteriorated rapidly, the respiration rate rose although the vomiting became less -frequent, and he died in the early hours of Jan. 16.Necropsy.-This was performed 36 hours after death. On opening the chest it was noticed that the left lung was collapsed. This collapse was old-standing. The pleural cavity was occupied by a mass of blood clot and what turned out to be omentum. In addition there was a loop of gangrenous stomach which had herniated through the diaphragm with a portion of omentum. The right lung ahowed oedema of the base and a little emphysema at the apex. The hernial orifice was well up towa'rds the mesial attachment of the muscle in the oesophageal opening. The herniated portion of the stomach was in the form of a well-marked diverticulum. No gross ulceration of vessels could be found in the stomach wall, and there is little doubt that there had been a generalized oozing from the strangulated portion of the stomach ...

MEDICAL MEMORANDA MBDICAL JOURNAL July 5.-The patient regained consciousness and became quieter.The neck rigidity persisted, but the temperature had dropped to 99.4°F. July 6.-Temperature normal; patient able to talk rationally and take nourishment. The strabismus and inequality of pupils disappeared and the facial paresis cleared up.July 8.-The patient received the last injection of penicillin at 4 p.m., and by 8 p.m. he developed a marked oedema of the anterior aspect of the neck, extending from the root of the neck to the thyroid cartilage. The temperature had risen to 99.2' F. The neck rigidity was still present; but was much less marked. Sulphadiazine 1 g. was given 4-hourly, and by the next morning the oedema had subsided.