PAI-1 deficiency attenuates the fibrogenic response to ureteral obstruction

BACKGROUND: Progressive renal disease is characterized by the induction of plasminogen activator inhibitor-1 (PAI-1), suggesting that impaired activity of the renal plasmin cascade may play a role in renal fibrosis. METHODS: To test this hypothesis, the severity of renal fibrosis caused by unilateral ureteral obstruction (UUO) was compared in PAI-1 wild-type (+/+) and PAI-1 deficient (-/-) mice. The extent of interstitial inflammation and fibrosis, renal plasminogen activator and plasmin activity, and renal expression of profibrotic genes was evaluated after 3, 7, and 14 days of UUO. RESULTS: Renal PAI-1 mRNA levels increased 8- to 16-fold in the +/+ mice after UUO surgery, and PAI-1 protein was detected in kidney homogenates. Interstitial fibrosis was significantly attenuated in -/- mice compared with +/+ mice at day 7 and day 14, based on the interstitial area stained with picrosirius red and total kidney collagen content. However, neither the mean renal plasminogen activator nor plasmin activities were increased in -/- mice compared with +/+ mice. The number of interstitial macrophages were significantly lower in the -/- mice three and seven days after UUO; interstitial myofibroblasts were significantly fewer at three days. At the same time points, this altered interstitial cellularity was associated with a significant reduction in renal mRNA levels for transforming growth factor-beta and procollagens alpha 1(I) and alpha 1(III). CONCLUSIONS: These studies establish an important fibrogenic role for PAI-1 in the renal fibrogenic response. The results demonstrate that one important fibrosis-promoting function of PAI-1 is its role in the recruitment of fibrosis-inducing cells, including myofibroblasts and macrophages.     

Paleocene latitude of the Kohistan–Ladakh arc indicates multistage India–Eurasia collision

We report paleomagnetic data showing that an intraoceanic Trans-Tethyan subduction zone existed south of the Eurasian continent and north of the Indian subcontinent until at least Paleocene time. This system was active between 66 and 62 Ma at a paleolatitude of 8.1 ± 5.6 °N, placing it 600–2,300 km south of the contemporaneous Eurasian margin. The first ophiolite obductions onto the northern Indian margin also occurred at this time, demonstrating that collision was a multistage process involving at least two subduction systems. Collisional events began with collision of India and the Trans-Tethyan subduction zone in Late Cretaceous to Early Paleocene time, followed by the collision of India (plus Trans-Tethyan ophiolites) with Eurasia in mid-Eocene time. These data constrain the total postcollisional convergence across the India–Eurasia convergent zone to 1,350–2,150 km and limit the north–south extent of northwestern Greater India to <900 km. These results have broad implications for how collisional processes may affect plate reconfigurations, global climate, and biodiversity.

Classically, the India–Eurasia collision has been considered to be a single-stage event that occurred at 50–55 million years ago (Ma) (1, 2). However, plate reconstructions show thousands of kilometers of separation between India and Eurasia at the inferred time of collision (3, 4). Accordingly, the northern extent of Greater India was thought to have protruded up to 2,000 km relative to present-day India (5, 6) (Fig. 1). Others have suggested that the India–Eurasia collision was a multistage process that involved an east–west trending Trans-Tethyan subduction zone (TTSZ) situated south of the Eurasian margin (7–9) (Fig. 1). Jagoutz et al. (9) concluded that collision between India and the TTSZ occurred at 50–55 Ma, and the final continental collision occurred between the TTSZ and Eurasia at 40 Ma (9, 10). This model reconciles the amount of convergence between India and Eurasia with the observed shortening across the India–Eurasia collision system with the addition of the Kshiroda oceanic plate. Additionally, the presence of two subduction systems can explain the rapid India–Eurasia convergence rates (up to 16 mm a⁻¹) that existed between 135 and 50 Ma (9), as well as variations in global climate in the Cenozoic (11).Open in a separate windowFig. 1.The first panel is an overview map of tectonic structure of the Karakoram–Himalaya–Tibet orogenic system. Blue represents India, red represents Eurasia, and the Kohistan–Ladakh arc (KLA) is shown in gray. The different shades of blue highlight the deformed margin of the Indian plate that has been uplifted to form the Himalayan belt, and the zones of darker red within the Eurasian plate highlight the Eurasian continental arc batholith. Thick black lines denote the suture zones which separate Indian and Eurasian terranes. The tectonic summary panels illustrate the two conflicting collision models and their differing predictions of the location of the Kohistan–Ladakh arc. India is shown in blue, Eurasia is shown in red, and the other nearby continents are shown in gray. Active plate boundaries are shown with black lines, and recently extinct boundaries are shown with gray lines. Subduction zones are shown with triangular tick marks.While the existence of the TTSZ in the Cretaceous is not disputed, the two conflicting collision models make distinct predictions about its paleolatitude in Late Cretaceous to Paleocene time; these can be tested using paleomagnetism. In the single-stage collision model, the TTSZ amalgamated with the Eurasian margin prior to ∼80 Ma (12) at a latitude of ≥20 °N (13, 14). In contrast, in the multistage model, the TTSZ remained near the equator at ≤10 °N, significantly south of Eurasia, until collision with India (9) (Fig. 1).No undisputed paleomagnetic constraints on the location of the TTSZ are available in the central Himalaya (15–17). Westerweel et al. (18) showed that the Burma Terrane, in the eastern Himalaya, was part of the TTSZ and was located near the equator at ∼95 Ma, but they do not constrain the location of the TTSZ in the time period between 50 and 80 Ma, which is required to test the two collision hypotheses. In the western Himalaya, India and Eurasia are separated by the Bela, Khost, and Muslimbagh ophiolites and the 60,000 km² intraoceanic Kohistan Ladakh arc (19, 20) (Fig. 1). These were obducted onto India in the Late Cretaceous to Early Paleocene (19), prior to the closure of the Eocene to Oligocene Katawaz sedimentary basin (20) (Fig. 1). The Kohistan–Ladakh arc contacts the Eurasian Karakoram terrane in the north along the Shyok suture and the Indian plate in the south along the Indus suture (21) (Fig. 1). Previous paleomagnetic studies suggest that the Kohistan–Ladakh arc formed as part of the TTSZ near the equator in the early Cretaceous but provide no information on its location after 80 Ma (22–25). While pioneering, these studies lack robust age constraints, do not appropriately average paleosecular variation of the geodynamo, and do not demonstrate that the measured magnetizations have not been reset during a subsequent metamorphic episode.     

A human amphotropic retrovirus receptor is a second member of the gibbon ape leukemia virus receptor family.

Retrovirus infection is initiated by binding of the viral envelope glycoprotein to a cell-surface receptor. The envelope proteins of type C retroviruses of mammals demonstrate similarities in structural organization and protein sequence. These similarities suggest the possibility that retroviruses from different interference groups might use related proteins as receptors, despite the absence of any relationship between retrovirus receptors isolated to date. To investigate this possibility, we have identified a human cDNA clone encoding a protein closely related to the receptor for gibbon ape leukemia virus and have found that it functions as the receptor for the amphotropic group of murine retroviruses. Expression of this protein (GLVR-2) is likely to be a requirement for infection of human cells by amphotropic retroviral vectors for purposes of gene therapy.     

Severe isolated aortic stenosis with normal left ventricular systolic function and low transvalvular gradients: pathophysiologic and prognostic insights

BACKGROUND AND AIM OF THE STUDY: A significant proportion of patients with severe valvular aortic stenosis (AS) and preserved left ventricular (LV) systolic function have low transvalvular gradients. The study aim was to determine the mechanisms and outcome of patients with this hemodynamic profile of AS. METHODS: Among 1,679 patients who underwent transthoracic echocardiography for the evaluation of AS at the authors' institution, 215 (105 females, 110 males; mean age: 77 +/- 10 years) had isolated AS (mean aortic valve area index 0.39 +/- 0.1 cm2/m2), normal sinus rhythm and normal LV ejection fraction. The mean follow up was 23 +/- 12 months, and the end-points were mortality, aortic valve replacement (AVR), or mortality or AVR. RESULTS: Forty-seven patients had a transvalvular mean gradient (MG) <30 mmHg (MG(low)) and 168 had MG > or = 30 mmHg (MG(high)). Compared to MG(high), the MG(low) group had a higher prevalence of hypertension, lower LV end-diastolic volume index (47 +/- 9 versus 56 +/- 12 ml/m2, p <0.0001), lower LV stroke vol-ume index (37 +/- 12 versus 41 +/- 11 ml/beat, p <0.0002), a lesser severity of stenosis (aortic valve area index 0.37 +/- 0.09 versus 0.46 +/- 0.09 cm2/m2, p <0.0001) and a higher systemic vascular resistance (2163 +/- 754 versus 1879 +/- 528 dyne cm s(-5). The LV end-diastolic volume index, systemic vascular resistance and energy loss index were predictors of MG <30 mmHg (OR = 0.30, 95% CI, 0.12, 0.62; OR = 3.05, 95% CI, 1.71, 6.26; and OR = 6.76, 95% CI, 3.44,15.38, respectively). MG <30 mmHg (MGhigh) was associated with almost 50% lower referral to surgery and a two-fold increase in preoperative mortality. CONCLUSION: In severe AS with a normal LV ejection fraction, MG <30 mmHg is related to a lesser severity of stenosis, a smaller LV volume, a lower flow rate and a higher systemic vascular resistance. Compared to the MG(high) group, these patients were less frequently referred to surgery and had a higher mortality.     

Eccentric and concentric torque-velocity characteristics of the quadriceps femoris in man

Summary The primary purpose of this investigation was to study the eccentric and concentric torque-velocity characteristics of the quadriceps femoris in man using a recently developed combined isometric, concentric and eccentric controlled velocity dynamometer (the SPARK System). A secondary purpose was to compare the method error associated with maximal voluntary concentric and eccentric torque output over a range of testing velocities. 21 males (21–32 years) performed on two separate days maximal voluntary isometric, concentric and eccentric contractions of the quadriceps femoris at 4 isokinetic lever arm velocities of 0° · s^–1 (isometric), 30° · s^–1 120° · s^–1 and 270° · s^–1. Eccentric peak torque and angle-specific torques (measured every 10° from 30° to 70°) did not significantly change from 0° · s^–1 to 270° · s^–1 (p>0.05) (with the exception of angle-specific 40° torque, which significantly increased;p<0.05). The mean method error was significantly higher for the eccentric tests (10.6%±1.6%) than for the concentric tests (8.1%±1.7%) (p<0.05). The mean method error decreased slightly with increasing concentric velocity (p>0.05), and increased slightly with increasing eccentric velocity (p>0.05). A tension restricting neural mechanism, if active during maximal eccentric contractions, could possibly account for the large difference seen between the present eccentric torque-velocity results and the classic results obtained from isolated animal muscle.