Left ventricular pressure effects on right ventricular pressure and volume outflow

Massive destruction of the right ventricular free wall has been shown to cause only mild hemodynamic alterations. Further, the derivative of right ventricular (RV) pressure (P) is broad or double peaked, with one peak occurring coincidentally with peak left ventricular (LV) dP/dt. Both observations suggest a direct LV assistance to RV function. Since the ventricles contract nearly simultaneously, the relative contribution of LV to RV pump function has been difficult to determine. This LV assistance was quantified in six canine experiments using a unique electrically isolated RV preparation. While on total cardiopulmonary bypass, the RV free wall was electrically isolated from the remainder of the heart. This preparation allowed for wide variations in the timing interval between RV and LV contractions. Double-peaked waveforms for RVP and pulmonary flow (RVF) occurred over a wide range (0 to 300 ms) of pacing intervals between the RV and LV. One derivative peak always followed RV contraction for RVP and RVF (r = 0.971 +/- .011, P less than 0.01: r = 0.972 +/- .012, p less than 0.01; respectively). The second derivative peak was unrelated to the RA-RV pacing interval (r = 0.297 +/- .191, P greater than 0.5 RVP; 4 = 0.237 +/- .278, P greater than 0.5 RVF), but corresponded to the maximal LVP rise. Additionally, the magnitude of the two derivative peaks was similar when the ventricles contracted synchronously. When RV contraction preceded or followed LV contraction, the derivative peak associated with LV contraction was significantly greater (P less than 0.05, range 2.1 +/- 0.6 to 6.7 +/- 1.6 for RVP; P less than 0.05 range 1.9 +/- 0.4 to 6.7 +/- 1.5 for RVF) than the derivative associated with RV contraction. These data demonstrate a normally present, large LV assistance to RV contraction and may help to explain the RV response to myocardial infarction.     

Ultrastructure of electrophysiologically identified human sinoatrial nodes

Summary The ultrastructure of freshly excised human sinus node tissue was studied. In three female patients (ages 20, 30, and 36 years) medically refractory disabling episodes of inappropriate sinus tachycardia were surgically treated by extirpation of the sinus node. Each patient underwent intraoperative electrophysiological mapping to determine the area of earliest atrial activation. This area corresponded anatomically to the region of the sinoatrial node and was excised in each patient, the defect repaired using a pericardial patch. The freshly excised SA nodes underwent ultrastructural study. Three types of myocardial cells were identified: pacemaker or polygonal cells with clear cytoplasm, few mitochondria and sparse numbers of contractile elements (P cells); a transitional cell with slightly increased numbers of myofibrils (T cells); and typical atrial myocardial cells with normal numbers of contractile elements. These cell types have previously been identified in post-mortem studies of presumed SA node. The current study confirms the cell types in electrophysiologically documented SA nodes. The one abnormal finding observed in transitional cells in all patients was an increased number of lipofuscin-laden vacuoles. These vacuoles are considered a sign of cell degeneration and their occurrence was totally unexpected in these young adults. In summary, ultrastructural study of electrophysiologically documented human SA nodes confirmed the cell types identified in post-mortem studies. Furthermore, lipofuscin-laden vacuoles were increased in these three patients and this finding may serve as an ultrastructural marker associated with the syndrome of inappropriate sinus tachycardia.Supported in part by: NIH HL 32086, HL 17678, HL 09315     

The bioavailability of benorylate in hot beverages.

It has been recommended that benorylate may be administered with hot beverages to overcome the problem of its relative unpalatability. Urine salicylate recovery used as a measure of bioavailability in 20 normal subjects has shown that hot coffee has no significant effect on drug availability from the orally administered suspension.     

Gene expression changes associated with Barrett's esophagus and Barrett's-associated adenocarcinoma cell lines after acid or bile salt exposure

Background  

Esophageal reflux and Barrett's esophagus represent two major risk factors for the development of esophageal adenocarcinoma. Previous studies have shown that brief exposure of the Barrett's-associated adenocarcinoma cell line, SEG-1, or primary cultures of Barrett's esophageal tissues to acid or bile results in changes consistent with cell proliferation. In this study, we determined whether similar exposure to acid or bile salts results in gene expression changes that provide insights into malignant transformation.     

Suprasellar germ cell tumours: specific problems and the evolution of optimal management with a combined chemoradiotherapy regimen

OBJECTIVE: Suprasellar germ cell tumours are rare, and there are few series of patients outlining the problems in diagnosis and management, and providing clear guidelines for optimal therapy. We have therefore reviewed our own series of 11 such patients who were managed in a joint endocrinology/clinical oncology setting. PATIENTS AND DESIGN: A retrospective case review assessment of all patients seen within a given time. Clinical, biochemical and radiological findings were reviewed, the types of therapy administered noted, and the responses to treatment analysed. RESULTS: In the years 1977-2001, 11 patients with suprasellar (SS) germ cell tumours (GCT) were seen (germinomatous : nongerminomatous = 8 : 3). SSGCT had an approximately equal sex incidence (M : F, 6 : 5), in contrast to pineal tumours, the commonest site of origin of intracranial GCT and which occur predominantly in men. The median age at presentation was 20 years (range 6-49 years) with a median duration of symptoms before diagnosis of 17 months (range 1-35 months). Polyuria was the commonest presenting symptom (10 patients). Diabetes insipidus occurred in all patients, as did partial or complete anterior pituitary failure. Visual failure was present in 55% of cases. Anorexia, weight loss and disturbed thirst sensation were also common. Positron emission tomography scanning was occasionally useful in the evaluation of suprasellar tumours/pituitary stalk lesions deemed too risky to biopsy. A "central nervous system-friendly" chemoradiotherapy regimen comprising vincristine, etoposide and carboplatin and differential daily dose irradiation, usually administered using a partial transmission block technique, produced a 5-year survival of 100% with low morbidity. Treatment did not correct previously abnormal endocrine function although it did improve vision in three of six patients. CONCLUSIONS: We therefore emphasize the use of techniques other than biopsy in the diagnosis of these patients, note the problems in the management of their fluid control, and highlight the favourable response to a combined chemotherapy-radiotherapy protocol.     

Red blood cells mediate spontaneous aggregation of platelets in whole blood

The influence of red blood cells on spontaneous platelet aggregation (SPA) has been studied ex vivo. Platelet aggregation was quantified by measuring the fall in single platelet count using a new whole blood platelet counter. When aliquots of whole blood and autologous platelet rich plasma (PRP) were roller-mixed at 37 degrees C, a marked fall in platelet count occurred in whole blood due to SPA but platelet count remained almost unchanged in PRP. When blood from healthy young controls, aged 20-35 years, was compared with healthy old controls, aged 48-80 years, and patients with thrombotic complications, the extent of SPA was in the order: thrombotic patients greater than old controls greater than young controls. Prostacyclin and the new stable prostacyclin analogue Iloprost, at 8 nM effectively inhibited SPA. 2-Chloroadenosine (10 microM) which is an inhibitor of ADP-induced platelet aggregation was also an effective inhibitor of SPA. Acetylsalicylic acid (56 microM) and the thromboxane A2 receptor blocker BM13.177 (0.5 microM) only partially inhibited SPA. ADP from red blood cells is suspected to mediate red cell-induced SPA. However, the possibility that the red cells have an important physical role in SPA cannot be ruled out.     

The splicing-factor oncoprotein SF2/ASF activates mTORC1

The splicing factor SF2/ASF is an oncoprotein that is up-regulated in many cancers and can transform immortal rodent fibroblasts when slightly overexpressed. The mTOR signaling pathway is activated in many cancers, and pharmacological blockers of this pathway are in clinical trials as anticancer drugs. We examined the activity of the mTOR pathway in cells transformed by SF2/ASF and found that this splicing factor activates the mTORC1 branch of the pathway, as measured by S6K and eIF4EBP1 phosphorylation. This activation is specific to mTORC1 because no activation of Akt, an mTORC2 substrate, was detected. mTORC1 activation by SF2/ASF bypasses upstream PI3K/Akt signaling and is essential for SF2/ASF-mediated transformation, as inhibition of mTOR by rapamycin blocked transformation by SF2/ASF in vitro and in vivo. Moreover, shRNA-mediated knockdown of mTOR, or of the specific mTORC1 and mTORC2 components Raptor and Rictor, abolished the tumorigenic potential of cells overexpressing SF2/ASF. These results suggest that clinical tumors with SF2/ASF up-regulation could be especially sensitive to mTOR inhibitors.