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A transformation-sensitive human protein (IEF SSP 3521) that is 2-fold up-regulated in SV40-transformed MRC-5 fibroblasts has been purified by two-dimensional gel electrophoresis, microsequenced, and cDNA cloned using oligodeoxyribonucleotides. The 2.1-kilobase cDNA encodes a 543-amino acid protein with a calculated molecular mass of 62.6 kDa and a calculated pI of 6.77. Expression of the cDNA in AMA cells using the vaccinia virus expression system followed by two-dimensional gel electrophoresis showed that the protein comigrated with IEF SSP 3521. The protein contains the tetratricopeptide repeat found in families of fungal proteins required for mitosis and RNA synthesis. In particular, the protein has 42% amino acid sequence identity to STI1, a stress-inducible mediator of the heat shock response in Saccharomyces cerevisiae. Northern blot analysis indicated that the 3521 mRNA is up-regulated in several transformed cells. Immunofluorescence studies using a polyclonal antibody raised against the purified protein revealed that the antigen is present mainly in the nucleus of SV40 transformed MRC-5 fibroblasts, while it localizes to the Golgi apparatus and small vesicles in their normal counterparts. The possible physiological role of IEF SSP 3521 is discussed in the light of the structural relationship with STI1.
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MET, RON, and SEA are members of a gene family encoding tyrosine kinase receptors with distinctive properties. Besides mediating growth, they control cell dissociation, motility ("scattering"), and formation of branching tubules. While there are transforming counterparts of MET and SEA, no oncogenic forms of RON have yet been identified. A chimeric Tpr-Ron, mimicking the oncogenic form of Met (Tpr-Met) was generated to investigate its transforming potential. For comparison, a chimeric Tpr-Sea was also constructed. Fusion with Tpr induced constitutive activation of the Ron and Sea kinases. While Tpr-Sea was more efficient than Tpr-Met in transformation, Tpr-Ron did not transform NIH 3T3 cells. The differences in the transforming abilities of Tpr-Met and Tpr-Ron were linked to the functional features of the respective tyrosine kinases using the approach of swapping subdomains. Kinetic analysis showed that the catalytic efficiency of Tpr-Ron is five times lower than that of Tpr-Met. Moreover, constitutive activation of Ron resulted in activation of the MAP kinase signaling cascade approximately three times lower than that attained by Tpr-Met. However, constitutive activation of Ron did induce a mitogenic-invasive response, causing cell dissociation, motility, and invasion of extracellular matrices. Tpr-Ron also induced formation of long, unbranched tubules in tridimensional collagen gels. These data show that RON has the potential to elicit a motile-invasive rather than a transformed phenotype.
Transmission pressure ratio (TPR) analysis of urethral pressure profilometry data has been advocated for the diagnosis of genuine stress incontinence (GSI). However, the clinical usefulness of the technique has not been adequately evaluated. Using videourodynamics as the gold standard, the TPR results of 150 continent women and 153 with GSI have been compared. The mean TPR for each quartile of the functional urethral length was computed, as was the maximum TPR value (TPR-max) and the position on the urethra where it occurred (TPR-mode). There was a statistically significant difference between the 2 groups for TPR values in the distal 2 quartiles of the urethra and for TPR-max and TPR-mode. With the use of the Kappa statistic it was found that the TPR-mode was the most discriminatory of the TPR parameters. Even using this measure, the overlap between normal and GSI was so great as to make accurate diagnosis impossible. It was therefore concluded that TPR analysis is useless for the diagnosis of GSI. However, such an analysis is helpful for the understanding of the pathophysiology of GSI and its treatment.
Survival in acute leukaemia depends on the achievement of complete remission (CR). However, CR is not a clear-cut phenomenon and certain variables of its definition could more accurately characterize the quality of the remission. Because platelet recovery > 100 x 10(9)/l is an essential component of CR in acute leukaemia, we hypothesized that time to platelet recovery (TPR) might be predictive of overall survival (OS) or disease-free survival (DFS) in acute lymphoblastic leukaemia (ALL). We analysed TPR in 249 patients with ALL who entered CR after one course of induction chemotherapy and correlated TPR with DFS and OS. TPR was significantly associated with both DFS and OS if it occurred within a maximum of about 60 d from start of therapy. Furthermore, during that time period, the relative risk of death increased with increasing TPR. Although presence of the Philadelphia chromosome was the single most important adverse feature at diagnosis, the effect of TPR on survival continued to be significant within this patient subgroup. This effect was so pronounced that Philadelphia chromosome-positive patients with a TPR of 12 d had a better outcome than Philadelphia chromosome-negative patients with a TPR of 48 d. Thus, a short TPR seems to be able to override adverse characteristics in the outcome of ALL patients treated with chemotherapy. We conclude that a quicker TPR predicts longer DFS and OS in patients with ALL. As platelet counts are obtained almost daily in patients undergoing chemotherapy, TPR can readily be utilized to assess the prognosis of these patients.
Correlation between blood pressure (BP) and total peripheral vascular resistance (TPR), hypotensive mechanisms of calcium antagonists, and cardiovascular responses to norepinephrine with and without administration of calcium antagonists were investigated in normotensive and genetic essential hypertensive humans. Supine resting decreased BP, heart rate (HR), stroke volume (SV), and cardiac output (CO), and, in contrast, it increased TPR. After 1 h supine rest, BP was positively correlated with TPR (r = 0.710; number = 45, p less than 0.001), but it was not correlated with CO. Intravenous infusion of the calcium antagonist diltiazem lowered BP and TPR, without apparently affecting HR, SV, and CO. In contrast, the calcium antagonist nifedipine diminished BP and TPR while increasing HR, SV, and CO. Norepinephrine elevated BP and TPR and decreased HR, SV, and CO. Prior administration of nifedipine inhibited elevation of TPR after treatment with norepinephrine. In contrast, prior administration of propranolol did not inhibit norepinephrine-induced BP and TPR elevation. From the results it may be concluded that elevation of BP is dependent on alteration of TPR, but not CO, in essential hypertensive humans. The arterial vasodilating effects of calcium antagonists induce a fall in both TPR and BP and inhibit norepinephrine-induced TPR increase. This suggests that abnormal contraction and relaxation of systemic arterial smooth muscle is a primary cause of the development and persistence of high BP in genetic (main gene) essential hypertensive humans.
High-level (greater than 1,000 micrograms/ml) resistance to the antimicrobial agent trimethoprim was found in 17 of 101 (17%) coagulase-negative staphylococci and 5 of 51 (10%) Staphylococcus aureus from a number of different hospitals in the United States. Resistance was plasmid encoded and could be transferred by conjugation in 4 of the 17 (24%) Tpr coagulase-negative staphylococci and 3 of the 5 (60%) Tpr S. aureus. A 1.2-kilobase segment of plasmid DNA from one of the plasmids (pG01) was cloned on a high-copy-number vector in Escherichia coli and expressed high-level Tpr (MIC, 1,025 micrograms/ml) in the gram-negative host. In situ filter hybridization demonstrated homology between the cloned Tpr gene probe and plasmid DNA from each conjugative Tpr plasmid, a single nonconjugative plasmid from a United States Staphylococcus epidermidis isolate, a nonconjugative plasmid from an Australian methicillin-resistant S. aureus isolate, and chromosomal DNA from three Tpr S. epidermidis isolates that did not contain any plasmid DNA that was homologous with the probe. No homology was seen between the probe and staphylococcal plasmids not mediating Tpr, plasmid DNA from 12 Tpr S. epidermidis isolates not transferring Tpr by conjugation, or plasmid-encoded Tpr genes derived from gram-negative bacteria. Plasmid-encoded Tpr appears to be a relatively new gene in staphylococci and, because it can be transferred by conjugation, could become more prevalent in nonsocomial isolates.
OBJECTIVE: Total peripheral vascular resistance (TPR) decreases in thyrotoxicosis and increases in hypothyroidism. Several mechanisms may be involved, including adaptation to changes in heat production and direct non-genomic effects of tri-iodothyronine (T3) on vascular smooth muscle cells. The aim of this study was to see if changes in TPR are related to changes in plasma concentrations of the endothelial hormones adrenomedullin and endothelin-1 as well as other hormones affecting vasculature. DESIGN: A prospective study. SUBJECTS: Eleven hypothyroid patients (pretreatment: thyroid-stimulating hormone (TSH) 68 (38-201) mU/l, T3 0.7 (0.35-1.5) nmol/l, fT4 3.0 (2.0-5.9) pmol/l, median (range)) and 14 with hyperthyroidism (pretreatment: TSH 0.02 (<0.01-0.06) mU/l, T3 6.4 (2.3-13.0) nmol/l, fT4 56.1 (22.9-70.0) pmol/l) were studied before treatment and 3 months after reaching the euthyroid state. Blood collection was carried out simultaneously with the recording of finger arterial pressure (FINAP). Cardiac output and TPR were derived from stroke volume computations by modelling flow from the FINAP signal. RESULTS: Thyroid-function tests of hypothyroid and thyrotoxic patients did not differ after restoration of the euthyroid state. TPR, expressed in arbitrary units (AU), decreased after correction of hypothyroidism (from 1.32+/-0.65 to 0.96+/-0.36 AU, P=0.04) and increased after correction of hyperthyroidism (from 0.75+/-0.18 to 1.10+/-0.35 AU, P=0.007). Adrenomedullin concentrations did not change during the transition from the hypothyroid state 3.2(0.9-11.0) pmol/l to the euthyroid state 4.9(0.9-8.6) pmol/l, but decreased after treatment of hyperthyroidism, from 5.2(0.9-11.0) pmol/l to 2.2(0.9-5.4) pmol/l. Plasma endothelin-1 was undetectable in all samples. Changes in TPR upon treatment correlated with log DeltafT4 (r=-0.65, P=0.001), log DeltaT3, (r=-0.57, P=0.006), Delta noradrenaline (r=0.54, P=0.02) and Delta ANP (atrial natriuretic peptide) (r=-0.59, P=0.004). Multiple linear regression analysis indicated that only T3 was an independent determinant of TPR. Changes in T3 accounted for 46% of the variability in the changes in TPR. CONCLUSIONS: TPR is reduced in thyrotoxicosis and increased in hypothyroidism. Restoration of the euthyroid state normalizes TPR. Changes in TPR are not related to plasma adrenomedullin concentrations, but 46% could be explained by changes in T3. Altered ANP secretion and adrenergic tone may contribute to the T3-induced changes in TPR.
A cross-sectional analysis of associations between total plasma renin (TPR) and aldosterone, blood pressure, renal haemodynamics, autonomic function and electrolyte balance was carried out in 35 hypertensive non-azotaemic insulin-dependent diabetics. Supine TPR was increased in 10 subjects and reduced in one, although erect TPR was increased in nine but reduced in 18 subjects. The supine to erect TPR gradient was greater than 40% in all cases. Supine and erect TPR correlated closely (r = 0.99, P less than 0.001). No correlation was found between TPR and age or blood pressure and multiple regression analysis failed to reveal independent predictors for TPR. Supine aldosterone was reduced in two subjects and increased in three, and erect aldosterone levels were reduced in three but increased in eight subjects. However, the postural aldosterone gradient was greater than 40% in only 20 cases. Supine and erect aldosterone correlated with each other (rs = 0.64, P = 0.001) but not with TPR. Aldosterone levels were most strongly related inversely to duration of diabetes, diabetic retinopathy, parasympathetic neuropathy and directly to diastolic blood pressure and glomerular filtration rate. Aldosterone levels correlated negatively with age. This was corrected for in multiple regression analysis which revealed an inverse relationship between supine aldosterone and serum potassium (P less than 0.05) and a direct one with renal plasma flow (P less than 0.007). Erect aldosterone was independently associated with duration of diabetes (P less than 0.005), systolic postural gradient (P less than 0.02), and the postural aldosterone gradient with the presence of parasympathetic neuropathy (P less than 0.004). The observation of elevated TPR in 10 subjects and the lack of relationship between TPR and other variables may reflect the overproduction of inactive relative to active renin in insulin-dependent hypertensive diabetics with autonomic dysfunction. The association between aldosterone and blood pressure, renal haemodynamics and electrolyte balance suggests that mineralocorticoids may be relevant to the natural history of hypertensive diabetic renal disease.
The SPINDLY (SPY) protein of Arabidopsis is a negative regulator of gibberellin (GA) response. The SPY protein has 10 copies of the tetratricopeptide repeat (TPR) at the N terminus. TPR motifs function as protein-protein interaction domains. Several spy alleles are affected only in the TPR region suggesting that protein-protein interactions mediated by this domain are important for proper GA signaling. We have used a reverse genetics approach to further investigate the role of the TPR domain. The TPR domain of SPY was overexpressed in wild-type, gai, and spy plants. Expression of the TPR domain alone is not sufficient to rescue spy mutants. Expression of the TPR domain in a wild-type background produces phenotypes similar to those caused by loss-of-function spy mutants including resistance to GA biosynthesis inhibitors, short hypocotyl length, and early flowering. The dwarfing of the floral shoot internodes caused by the gai mutation was suppressed by expression of the TRP domain. Expression of the TPR domain had no effect on the abundance of endogenous SPY mRNA. The TPR domain was found to interact with SPY both in vitro and in yeast two-hybrid assays. These data indicate that the TPR domain of SPY can participate in protein-protein interactions and that these interactions are important for the proper functioning of SPY.
Beat-by-beat estimates of total peripheral resistance (TPR) can be obtained from continuous measurements of cardiac output by using Doppler ultrasound and noninvasive mean arterial blood pressure (MAP). We employed transfer function analysis to study the heart rate (HR) and vascular response to spontaneous changes in blood pressure from the relationships of systolic blood pressure (SBP) to HR (SBP-->HR), MAP to total peripheral resistance (TPR) and cerebrovascular resistance index (CVRi) (MAP-->TPR and MAP-->CVRi), as well as stroke volume (SV) to TPR in nine healthy subjects in supine and 45 degrees head-up tilt positions. The gain of the SBP-->HR transfer function was reduced with tilt in both the low- (0.03-0.15 Hz) and high-frequency (0.15-0.35 Hz) regions. In contrast, MAP-->TPR transfer function gain was not affected by head-up tilt, but it did increase from low- to high-frequency regions. The phase relationships between MAP-->TPR were unaffected by head-up tilt, but, consistent with an autoregulatory system, changes in MAP were followed by directionally similar changes in TPR, just as observed for the MAP-->CVRi. The SV-->TPR had high coherence with a constant phase of 150-160 degrees. Together, these data that showed changes in MAP preceded changes in TPR, as well as a possible link between SV and TPR, are consistent with complex interactions between the vascular component of the arterial and cardiopulmonary baroreflexes and intrinsic properties such as the myogenic response of the resistance arteries.