C4d Deposition and Clearance in Cardiac Transplants Correlates With Alloantibody Levels and Rejection in Rats

Antibody-mediated rejection of human cardiac transplants is correlated with C4d deposits and macrophage infiltrates in capillaries of endomyocardial biopsies. We produced an antibody to rat C4d to study C4d deposition and clearance in Lewis rats that were sensitized with a blood transfusion from DA rats 7, 14 or 21 days before cardiac transplantation. Cyclosporin A (CsA) immunosuppression was initiated after transplantation at a dose that inhibited graft rejection, antibody production and C4d deposition in unsensitized recipients. Blood transfusion elicited high levels of circulating IgG alloantibodies, predominantly of the complement-activating IgG2b subclass, that peaked 14 days after transplantation. At this time, macrophages accumulated in capillaries, and C4d deposits were diffuse and intense on arteries, capillaries and veins. Grafts that survived 90 days in sensitized recipients still had deposits of C4d that were associated with increased interstitial fibrosis and vasculopathy in arteries. Clearance of C4d was determined by retransplanting DA cardiac allografts from Lewis recipients back to DA recipients. C4d deposits were decreased to minimal levels within 5 days after retransplantation. Thus, C4d deposition is not limited to the capillaries, but extends throughout the arterial tree, and despite formation of a covalent bond, C4d is cleared within days.     

Prospective Study of Unplanned Admission to the Intensive Care Unit after Total Hip Arthroplasty

The morbidity associated with elective total hip arthroplasty (THA) may result in intensive care unit (ICU) admission. A total of 175 consecutive THA patients were prospectively triaged to either an ICU bed or routine post-operative floor according to admission criteria based on a prior published study of 1259 THA patients. Primary end points were a reduction in unplanned ICU admission, as well as major complications. With our triage model, the rate of unplanned ICU admissions dropped from 7.1% to 2.2% (P = 0.013). The as-treated odds of unplanned admission pre- versus post-intervention were 3.2 (1.2, 10.6). The complication rate fell from 12.5% to 2%, and the mortality index decreased from 4.77 to 1.62. Triage according to selected risk factors affects a reduction in unplanned ICU admissions and major complications after THA.     

Slower Onset of Low Shear Stress Leads to Less Neointimal Thickening in Experimental Vein Grafts

Vein grafts respond to low flow and shear stress (τ_w) by generating thicker walls and smaller lumens through the processes of neointimal hyperplasia and remodeling. Clinically, however, vein grafts with obviously low τ_w, such as those distal to high-grade proximal obstructions, are not infrequently found to be widely patent and pliable. One possible explanation for this phenomenon may be that vein grafts remodel more favorably in response to changes in shear that occur gradually over time compared to abruptly. This hypothesis was tested in an experimental animal model in this report. Two separate models of experimental vein graft failure were created, causing either immediate exposure to ultralow τ_w (<1 dyne/cm²) or delayed exposure to ultralow τ_w. Under general anesthesia and using a sterile technique, the right external jugular (EJ) veins of 28 New Zealand white rabbits were surgically exposed and isolated. An end-to-side distal EJ/common carotid artery anastomosis was created, resulting in a widely patent arteriovenous fistula. For the immediate exposure group (n = 5), the EJ was suture-ligated just proximal to the thoracic inlet, distal to a small 10-50 μm venous tributary. This created a reversed vein segment immediately and abruptly exposed to high wall tension (2.0 ± 0.3 × 10⁴ dyne/cm) and ultralow τ_w (0.15 ± 0.08 dyne/cm²). For the delayed exposure group (n = 22), the EJ was ligated over a 0.035 guidewire, leaving a small aperture to sustain some measure of blood flow and τ_w. This predictably resulted in slightly less wall tension (1.4 ± 0.2 × 10⁴ dyne/cm) and higher τ_w (0.68 ± 0.21 dyne/cm²) than the immediate exposure group. During the first week, the small outflow aperture in the delayed exposure grafts thrombosed, eventually exposing them to the same low level of τ_w as the immediate exposure grafts. Thus, the only difference in the two models was that delayed exposure grafts enjoyed a slower decline in τ_w than immediate exposure grafts. Fourteen rabbits in the delayed exposure group were harvested over the first 7 days to define the patency curve of the restricted outflow channel. As expected, the small aperture had thrombosed in all animals by 7 days. The remaining 14 grafts were harvested after 4 weeks, and 13/14 remained patent. Examination of the hemodynamic parameters at the time of death confirmed that wall tension and τ_w had equalized (wall tension 0.9 ± 0.1 vs. 1.1 ± 0.1 × 10⁴ dyne/cm, τ_w 0.45 ± 0.12 vs. 0.30 ± 0.08 dyne/cm²). Histological examination revealed less neointimal hyperplasia in the delayed exposure group compared to the immediate exposure group (wall thickness 266 ± 16 vs. 180 ± 24 μm, p = 0.025) as well as a slightly greater luminal diameter (0.30 ± 0.02 vs. 0.40 ± 0.02 cm, p = 0.038). The results of this experiment suggest that slow exposure to reduced τ_w results in more favorable remodeling (less thickening) than abrupt exposure. This finding may explain the occasional clinical observation of a widely patent vein graft even in the face of proximal arterial obstruction and very low flow; the change in τ_w presumably occurred slowly mitigating the remodeling response. Presented at the Vascular Society 2004 Annual Meeting, Anaheim, CA, June 5, 2004.     

Proteinuria in IgA nephropathy

Clinicopathological data in 74 patients with IgA nephropathy were analyzed with special attention to level of proteinuria and its prognostic significance in this disease. Excretion rates exceeding 3 g per day (heavy), in the range of 1 to 2.9 g (moderate) and under 1 g per day (mild) each occurred in approximately equal proportions of patients. One-sixth of those with more than 1 g developed end-stage renal failure, while serum creatinine never exceeded 2 mg/dl in any with mild proteinuria. "Renal survival" (serum creatinine of 2 mg/dl or less) at five years after presentation was 100% in patients with persistently mild proteinuria, 87% in those whose protein excretion reached the moderate range, and 69% when heavy or nephrotic range proteinuria developed. Of significance, only rarely did mild proteinuria at presentation increase to higher levels. A correlation existed between level of protein excretion and severity of mesangial, segmental or global proliferation, glomerulosclerosis, podocyte effacement, interstitial infiltration, tubular atrophy and vascular sclerosis, even in patients with unimpaired renal function. Moderate or heavy proteinuria typically preceded the onset of hypertension and occurred prior to the development of renal insufficiency. Our results underscore magnitude of proteinuria as an early marker of glomerular damage in the prognosis of IgA nephropathy.     

维A类化合物4-APR抑制肿瘤侵袭、转移的作用

用体内外实验模型,研究了新维A类化合物4-乙酰胺苯基维A酸酯(4-APR)对肿瘤侵袭、转移的抑制作用。4-APR 43.3mg·kg^-1po即能减少小鼠Lewis肺癌的自发性肺转移瘤数。半体内实验证明4-APR10^-5mol·L^-1和10^-6mol·L^-1对B16-F10癌细胞的人工肺转移瘤数分别抑制67.9%和36.6%。体外实验显示,4-APR对B16-F10细胞侵袭重组基底膜的抑制率分别为54.2%和41.9%。     

Patient preference for chronic obstructive pulmonary disease (COPD) treatment inhalers: a discrete choice experiment in France

Objectives: Understanding inhaler preferences may contribute to improving adherence in COPD patients and improving long-term outcomes. This study aims to identify and quantify preferences for convenience-related inhaler attributes in French moderate-to-severe COPD patients, with discrete choice experiment (DCE) methodology.

Methods: Attributes were defined from a literature search, clinician and patient interviews: shape, dose insertion, dose preparation, dose release, dose confirmation, dose counter and reusability. An online DCE was conducted in respondents with self-reported COPD stage 2–4 recruited through a panel. The study questionnaire included twelve choice scenarios per respondent and questions on patient characteristics, treatment and disease severity. Statistical analyses used a mixed logit regression model with random effects. Utility scores were estimated for four types of inhalers: Inhaler A – soft mist inhaler; Inhaler B – reusable soft mist inhaler; Inhaler C – multi-dose dry powder inhaler; and Inhaler D – single dose dry powder inhaler.

Results: The study was completed by 153 patients (50 females); respondents were 50.4?years old on average; 13 different inhaler devices were reported. The most preferred inhaler is L-shaped, has dose preparation with capsule insertion and a dose counter, and is reusable. Inhaler profiles A and B had the highest utilities (mean of 1.2533 and 0.9578 respectively) compared to inhaler C (0.6315) and D (0.2200).

Conclusions: This study showed statistically significant results that the strongest drivers of preference in French users of inhalation devices for COPD are shape, dose counter and reusability. Convenience-related characteristics are important to patients and should be taken into account by clinicians prescribing these devices.