Enhancement of the transient-evoked otoacoustic emission produced by the addition of a pure tone in the guinea pig

Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase implicated in cell-matrix interaction and integrin signaling. It is well established that Tyr-397 is the FAK autophosphorylation site and Tyr-407, -576/577, -861, and -925 are the sites on murine FAK that are mediated by Src family kinases. To study how FAK is regulated by tyrosine phosphatase(s), cells overexpressing chicken FAK are treated with sodium vanadate. Both the phosphotyrosine content and the enzymatic activity of FAK are increased in response to vanadate. Interestingly, sustained FAK Tyr-576/577 and -863 phosphorylations are detected in vanadate-treated FAK overexpressors and are dependent on FAK autophosphorylation. Further analysis of sodium vanadate-treated FAK overexpressors reveals that the enhanced FAK kinase activity parallels its elevated Tyr-576/577 phosphorylation. Thus, we conclude that Src-mediated FAK phosphorylation is regulated by a tyrosine phosphatase(s) and may be of physioligical significance.     

Low prevalence of coronary artery spasm in patients with normal coronary angiograms and unexplained ventricular fibrillation

AIMS: The aetiology of ventricular fibrillation in patients without identifiable structural heart disease is unknown. Recently, high prevalence of silent ischaemia due to coronary artery spasm has been reported in such patients. However, in at least one report, all patients had non-critical coronary artery lesions. Identification of coronary artery spasm as the underlying aetiology of ventricular fibrillation has important therapeutic implications. METHODS AND RESULTS: We performed ergonovine provocation tests in 18 patients (14 males, and four females; mean age, 36 years) with documented ventricular fibrillation in the absence of identifiable structural heart disease who had undergone aborted sudden death. In group I (n = 7) ergonovine provocation tests were performed at a mean interval of 31 months (range 21-42 months) after the index episode. These patients had already received an implantable cardioverter defibrillator, after failed electrophysiologically guided antiarrhythmic therapy. In group II (n = 11) the ergonovine provocation test was performed prospectively as part of the diagnostic evaluation. All patients were off antiarrhythmic drugs, calcium entry or beta-adrenoceptor blockers at the time of the ergonovine provocation test. Ergonovine was administered intravenously as a bolus injection, beginning with 0.05 mg followed every 3 min by incremental doses up to a cumulative maximum dose of 0.45 mg. Predefined end-points were (1) recording of ischaemic ST segment shifts of > or = 1 mm in at least two corresponding leads of the 12-lead electrocardiogram; (2) induction of ventricular tachycardia or ventricular fibrillation; and (3) administration of a cumulative dose of 0.45 mg. A positive response to ergonovine was seen in only one patient (5%) in group I in whom there developed ST segment elevation without angina and a short burst of rapid ventricular tachycardia. CONCLUSIONS: This study found a low prevalence of coronary artery spasm in patients with aborted sudden death resulting from documented ventricular fibrillation and non-apparent underlying heart disease. All patients had normal coronary angiograms and a negative history for spontaneous episodes of chest pain. The mechanism of arrhythmogenesis in such patients remains largely unknown.     

Contribution of plasminogen activators and their inhibitors to the survival prognosis of patients with Dukes' stage B and C colorectal cancer

Despite the advances in pre-, peri- and post-operative medical care of colorectal carcinoma patients, the prognosis has improved only marginally over recent decades. Thus, additional prognostic indicators would be of great clinical value to select patients for adjuvant therapy. In previous studies we found that colorectal carcinomas have a marked increase of the urokinase-type of plasminogen activator (u-PA), and the inhibitors PAI-1 and PAI-2, whereas the tissue-type plasminogen activator (t-PA) is found to be decreased in comparison with adjacent normal mucosa. In the present study we evaluated the prognostic value of several plasminogen activation parameters, determined in both normal and carcinomatous tissue from colorectal resection specimens, for overall survival of 136 Dukes' stage B and C colorectal cancer patients, in relation to major clinicopathological parameters. Uni- and multivariate analyses indicated that a high PAI-2 antigen level in carcinoma, a low t-PA activity and antigen level and a high u-PA/t-PA antigen ratio in adjacent normal mucosa are significantly associated with a poor overall survival. A high ratio of u-PA antigen in the carcinomas and t-PA antigen in normal mucosa, i.e. u-PA(C)/t-PA(N), was found to be predictive of a poor overall survival as well. All these parameters were found to be prognostically independent of the clinicopathological parameters. Multivariate analysis of combinations of these prognostically significant plasminogen activation parameters revealed that they are important independent prognostic indicators and have in fact a better prognostic value than their separate components. Based on these combined parameters, subgroups of patients with Dukes' stage B and C colorectal cancer could be identified as having either a high or a low risk regarding overall survival. In conclusion, these findings emphasize the relevance of the intestinal plasminogen activation system for survival prognosis of patients with colorectal cancer and, in the future, might constitute a patient selection criterion for adjuvant therapy.     

Antibody-mediated oligodendrocyte cell death requires an astrocyte-derived cosignal

The purpose of this study is to develop an experimental model to measure localized radiation-induced lung injury using multiple end-points including breathing frequency, high-resolution computed tomography (CT), and radionuclide perfusion. The rats were anesthetized and the right lung irradiated with a single dose of 18 Gy using 200-kVp x-rays. The lung function of the animals was measured every 2 weeks after irradiation with the breathing rate assay. CT scanning and radionuclide lung perfusion assay were performed prior to and 2, 4, 10, 16, and 34 weeks after irradiation. Significant elevation in breathing rate occurred after 16 weeks, with a maximal increase between 22 and 28 weeks. An increase in the right lung density started 4 weeks after irradiation. Regional measurements indicated a relatively uniform increase in density at 4 and 10 weeks, while foci of high-density areas were observed at the later time points. Changes in rat lung volume indicated shrinkage of the irradiated right lung and accompanying compensatory hypertrophy of the shielded left lung. Radionuclide perfusion assay showed significant decrease in relative blood flow in the irradiated right lung 4 weeks after hemithoracic irradiation. Changes in breathing rate provide an index of overall lung function while changes in lung density, volume, and perfusion are of particular importance for evaluating loco-regional differences in lung sensitivity. This study is the first demonstration that CT can be used to measure volume changes after thoracic irradiation in rats.     

Mullerian adenosarcoma of the uterine corpus associated with tamoxifen therapy: a report of six cases and a review of tamoxifen-associated endometrial lesions

Six consultation cases of mullerian adenosarcoma of the uterus were encountered in women who were receiving adjuvant tamoxifen therapy for carcinoma of the breast. To our knowledge, only one previous similar case has been reported. The women, who were 48-76 years of age, had received tamoxifen for periods of 6 months to 4 years (mean 2.7 years) in five of the cases; the duration of tamoxifen therapy in the sixth case is unknown. All of the tumors were polypoid endometrial masses that superficially invaded the myometrium in two cases. The microscopic appearance of the tumors was similar to that of previously described uterine mullerian adenosarcomas. These and other recent observations indicate that tamoxifen treatment may be complicated by uterine neoplasms other than endometrial adenocarcinoma. These findings also support previous observations that prolonged exogenous or endogenous hyperestrinism may lead to the development of mesenchymal and mixed epithelial-mesenchymal tumors of the uterus.     

Effect of metabolic acidosis on insulin action and secretion in uremia

BACKGROUND: Metabolic acidosis affects both vitamin D and insulin metabolism. Vitamin D is important in modulation of both insulin secretion and insulin sensitivity in uremia. The present study examines the effect of correction of metabolic acidosis on insulin action and secretion as well as 1,25 vitamin D3 concentrations in uremic patients. METHODS: Eight patients (age 18 +/- 1 year) on maintenance hemodialysis with metabolic acidosis were studied before and after two weeks of oral sodium bicarbonate (NaHCO3) treatment to correct the acidosis. To control for the effect of additional sodium, they were also studied after two weeks of an equivalent amount of oral sodium chloride (NaCl). Controls consisted of 7 healthy controls (age 19 +/- 1 year). Insulin sensitivity was measured by the hyperinsulinemic euglycemic clamp technique. Insulin secretion was measured by the hyperglycemic clamp technique. RESULTS: Oral NaHCO3 treatment led to significant increases in venous pH and serum bicarbonate concentrations but no significant change in intact parathyroid hormone (PTH) concentrations. Circulating 1,25 dihydroxyvitamin [(OH)2] D3 were significantly lower than control values initially and increased significantly after treatment. Oral NaCl did not change any of the biochemical parameters. Before treatment of acidosis, uremic patients had lower insulin sensitivity (insulin resistance) during constant hyperinsulinemia and lower insulin secretion during constant hyperglycemia compared with controls. Following two weeks of NaHCO3 treatment there were significant increases in insulin sensitivity and insulin secretion, although the values did not normalize. There were no changes in insulin sensitivity or insulin secretion following two weeks of NaCl. CONCLUSION: Treatment of metabolic acidosis increased both insulin sensitivity and insulin secretion in patients with uremia. This was accompanied by an increase in the circulating levels of 1,25(OH)2D3 but no change in those of parathyroid hormone.     

Chemical/biochemical detection of spoilage

Although sensory and/or microbiological analyses are widely relied on when assigning shelf-life of foods or trouble shooting problems with spoilage under storage, they do have drawbacks. Delay in obtaining results is one of them. The expense of the expert panels required to obtain meaningful sensory evaluations is another, while spoilage is not always of microbial origin. Even when it is, there are an increasing number of situations, including that of meats and fish packaged in modified atmospheres, where the relationships between microbial growth and spoilage onset is poorly defined. Chemical analysis has long been recognized as a means of circumventing at least some of the drawbacks and its potential is reviewed below. From the data presented it can be concluded that chemical characterization of spoilage processes is presently of most value in trouble shooting i.e. establishing the causes of spoilage. Its value in assigning total or remaining shelf-life requires more knowledge of the chemical processes leading to reduced acceptability/spoilage and of their correlations with sensory and microbiological changes.     

Extracorporeal membrane oxygenator support for cardiopulmonary failure. Experience in 28 cases

We have used extracorporeal membrane oxygenation (ECMO) for 28 patients (14 children and 14 adults) over a 5 year period. Nine patients improved on ECMO and 5 were long-term survivors. ECMO was used for pulmonary insufficiency in 24 patients. Initially, only moribund patients were treated, but recently the combination of open lung biopsy and pulmonary insufficiency index (PII) has been used to select patients. The best results have been obtained in newborn cases and the adult capillary leak syndromes; the major problem has been progression to fibrosis despite ECMO support. ECMO was used for cardiac failure in 4 patients. Children with postoperative cardiac failure did the best; profound shock was not reversed with venoarterial bypass. ECMO support is lifesaving in selected cases of pulmonary insufficiency. Initial trials in cardiac failure and the infant age group in this series suggest that ECMO will have an even greater role in those applications.     

The existence of a precursor of cathepsin D: evidence from autolysis, denaturation and activation studies

This report evidences that the single polypeptide chain of cathepsin D undergoes in vitro autolysis resulting in heavy (Mr about 30000) and light (Mr about 15000) polypeptide chains. These two chains are held together through non-covalent interaction, thus constituting a stable active conformation. Fluorescence and circular dichroism measurements demonstrate the irreversible denaturation of cathepsin D. The existence of cathepsin D precursor, cathepsinogen D, of about 50000 molecular weight was proved. Cathepsinogen D is converted to the active enzyme by intramolecular activation, releasing activation-inhibitory peptide(s).