The beneficial effects of recipient-derived vascular endothelial growth factor on graft survival after kidney transplantation

BACKGROUND: Vascular endothelial growth factor (VEGF) is crucial for preservation of microvasculature and contributes to cytoprotection of the graft after kidney transplantation. METHODS: The authors investigated the influence of VEGF single-nucleotide polymorphism (SNP) on graft survival after renal transplantation. The SNP at positions -2578, -1154, and, -7 were analyzed in 306 donors and 387 recipients of renal transplants. RESULTS: The authors observed no effect of those recipient or donor SNP on acute rejection. However, graft survival was associated with recipient SNP at position -2578 C/A. Recipients with a genetic basis for high production of VEGF had significantly better graft survival compared with recipients with low production of VEGF. Homozygotes for the A allele (low producers of VEGF) had worse graft survival compared with high producers, the heterozygotes and homozygotes for C allele (P=0.03). Multivariate analysis in which the effects of donor age, recipient race, cold ischemia time, donor origin, and number of human leukocyte antigen mismatches were included showed that the status of noncarriers of -2578 C allele of recipients was an independent factor for graft failure (odds ratio, 1.8; 95% confidence interval, 1.0-3.0; P=0.03). CONCLUSIONS: The authors conclude that homozygote recipients for the -2578 A allele, the low producers of VEGF, are more vulnerable to tissue injury, resulting in worse graft survival.     

Synthesis and properties of isocannabinoid and cholesterol derivatized rhamnosurfactants: application to liposomal targeting of keratinocytes and skin

The usefulness of vesicles to cargo material depends on the design of new ligands able to incorporate easily inside the bilayer and also to direct the vesicles to the targeted site. Therefore, the synthesis of two new rhamnose-bearing surfactants is described. The hydrophobic part consists of cholesterol (in compound 3) and citrylidene phloroglucinol (in compound 6). The ability of these two rhamnolipids to incorporate into a DPPC membrane and to form aggregates is investigated, respectively, by differential scanning calorimetry and by surface tension measurements. Those two new surfactants were incorporated in fluorescent liposomes to study their interactions with keratinocytes and skin sections. Intraliposomal delivery to keratinocytes was observed in both cases, even if the kinetics of delivery were different according to the rhamnosurfactant used. Skin sections were stained by both liposomal formulations, and different interactions between the liposomes and skin cells according to the surfactant used were noted.     

Performance monitoring in obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is associated with hyperactivity of brain structures involved in performance monitoring. It has been proposed that this pathophysiology results in the generation of inappropriate or excessive internal error signals, giving rise to the characteristic symptoms of OCD. We measured an electrophysiological correlate of performance monitoring, error-related negativity (ERN), to study whether OCD patients exhibit enhanced brain activity associated with errors and negative performance feedback. We found that OCD patients (n=16) and healthy control participants (n=16) did not differ in the amplitude of the ERN associated with errors and negative feedback in a probabilistic learning task. The discrepancy between these results and the results from previous studies is discussed.     

Accuracy of transvaginal ultrasonography in diabetic or obese women with postmenopausal bleeding

OBJECTIVE: We sought to assess the accuracy of endometrial thickness measurement in the diagnosis of endometrial cancer in patients with obesity, diabetes, and hypertension and to evaluate whether patient characteristics influence endometrial thickness irrespective of the final diagnosis. METHODS: This was a prospective study of women not using hormone replacement therapy who presented with postmenopausal bleeding at 8 hospitals in The Netherlands. All women underwent transvaginal ultrasonography and, in the event that the endometrial thickness (double layer) was more than 4 mm, subsequent endometrial sampling. The performance of endometrial thickness measurement in the diagnosis of atypical hyperplasia and endometrial cancer was evaluated in subgroups of patients with diabetes, hypertension, and obesity by using receiver operating characteristic analysis. RESULTS: Overall, we included 594 consecutive women, of whom 62 (10%) had endometrial carcinoma and 6 (1%) had atypical hyperplasia. In these women, transvaginal ultrasonography had an area under the receiver operating characteristic curve of 0.87 (standard error [SE] 0.03). In the absence of (pre)malignancy, women with diabetes or obesity were found to have thicker endometria than women without these risk factors, whereas in women with a (pre)malignancy, this difference was not present. The area under the receiver operating characteristic curve decreased to 0.74 (SE 0.05) and 0.75 (SE 0.07) in diabetic women and obese women, respectively. The presence or absence of hypertension had no impact on the accuracy of transvaginal ultrasonography. CONCLUSION: In view of the decreased diagnostic accuracy in diabetic women and obese women, the clinical value of transvaginal endometrial thickness measurement in these women is questionable.     

Medical management for termination of second and third trimester pregnancies: a comparison of strategies

OBJECTIVE: Misoprostol and sulprostone are prostaglandins that can be used for the termination of second and third trimester pregnancy. The aim of the present study was to compare the effectiveness of both agents for the termination of second and third trimester pregnancy in cases of congenital or genetic abnormalities, and for the induction of labour in cases of intra-uterine foetal death. STUDY DESIGN: We collected data from all women who had been treated with misoprostol in the second or third trimester of pregnancy between January 2001 and July 2002 in cases of congenital or genetic abnormalities, and for the induction of labour in cases of intra-uterine foetal death. In cases where the foetus was alive, misoprostol was usually (77%) combined with mifepristone. Women were matched to women who had been treated with sulprostone for termination of second and third trimester pregnancy before 2001. We matched for hospital, previous vaginal delivery, intra-uterine death and duration of pregnancy. The primary outcome measure was time to delivery. RESULTS: Since the treatment effect was different in patients in whom labour was induced for intra-uterine death and patients in whom labour was induced while the foetus was alive, the analysis was stratified for this parameter. In 94 patients with intra-uterine death, there was no significant difference in time to delivery, blood loss, operative removal of the placenta and need for pain relief between misoprostol and sulprostone. In vital pregnancy (n = 96), time to delivery was significantly shorter in the misoprostol group. The relative risk for haemorrhage exceeding 1000 ml in this group was 0.40 (95% confidence interval, CI, 0.13-1.2). We observed no significant differences with respect to operative removal of the placenta or need for pain relief. CONCLUSION: In cases of intra-uterine death, the effectiveness of misoprostol for termination of pregnancy is comparable to that of sulprostone. In vital pregnancy, combination of mifepristone and misoprostol is more effective than sulprostone alone.     

Grammont inverted total shoulder arthroplasty in the treatment of glenohumeral osteoarthritis with massive rupture of the cuff. Results of a multicentre study of 80 shoulders

We reviewed 80 shoulders (77 patients) at a mean follow-up of 44 months after insertion of a Grammont inverted shoulder prosthesis. Three implants had failed and had been revised. The mean Constant score had increased from 22.6 points pre-operatively to 65.6 points at review. In 96% of these shoulders there was no or only minimal pain. The mean active forward elevation increased from 73 degrees to 138 degrees. The integrity of teres minor is essential for the recovery of external rotation and significantly influenced the Constant score. Five cases of aseptic loosening of the glenoid and seven of dissociation of the glenoid component were noted. This study confirms the promising early results obtained with the inverted prosthesis in the treatment of a cuff-tear arthropathy. It should be considered in the treatment of osteoarthritis with a massive tear of the cuff but should be reserved for elderly patients.     

Fat embolism syndrome after surgery to replace the femoral stem of a hip prosthesis

A 66-year-old woman developed hemodynamic instability, oliguria, prostration, fever, and coagulopathy 4 hours after surgery to replace the femoral stem component of a hip prosthesis under a combined subarachnoid-epidural block. Dyspnea and tachypnea developed, and a petechial rash appeared 24 hours later. The diagnosis was fat embolism after other possible causes were ruled out. Supplementary oxygen, fluid replacement therapy, and inotropic support were started. The patient's condition improved and she was discharged from the postoperative recovery unit 5 days after admission. Although fat embolism usually appears in young men after large bone fractures, it should be considered when symptoms consistent with this diagnosis arise in patients who have undergone orthopedic surgery so that appropriate treatment can be started early.     

Haemodynamic effects of hyperbaric hyperoxia in healthy volunteers: an echocardiographic and Doppler study

In the present study, we observed the haemodynamic changes, using echocardiography and Doppler, in ten healthy volunteers during 6 h of compression in a hyperbaric chamber with a protocol designed to reproduce the conditions as near as possible to a real dive. Ambient pressure varied from 1.6 to 3 atm (1 atm=101.325 kPa) and partial pressure of inspired O2 from 1.2 to 2.8 atm. Subjects performed periods of exercise with breathing through a closed-circuit self-contained underwater breathing apparatus (SCUBA). Subjects did not eat or drink during the study. Examinations were performed after 15 min and 5 h. After 15 min, stroke volume (SV), left atrial (LA) diameter and left ventricular (LV) end-diastolic diameter (LVEDD) decreased. Heart rate (HR) and cardiac output (CO) did not vary, but indices of the LV systolic performance decreased by 10% and the LV meridional wall stress increased by 17%. After 5 h, although weight decreased, the serum protein concentration increased. Compared with values obtained after 15 min, SV and CO decreased, but LV systolic performance, LA diameter, LVEDD and LV meridional wall stress remained unchanged. Compared with the reference values obtained at sea level, total arterial compliance decreased, HR remained unchanged and CO decreased. In conclusion, hyperbaric hyperoxia results in significant haemodynamic changes. Initially, hyperoxia and the SCUBA system are responsible for reducing LV preload, increasing LV afterload and decreasing LV systolic performance, although CO did not change. Prolonged exposure resulted in a further decrease in LV preload, because of dehydration, and in a further increase in LV afterload, due to systemic vasoconstriction, with the consequence of decreasing CO.     

Structural insights into the conformational selectivity of STI-571 and related kinase inhibitors

STI-571 (Gleevec) is a highly successful cancer drug due to its activity as an inhibitor of the Abelson cytoplasmic tyrosine kinase (Abl), which is constitutively active in a majority of patients with chronic myelogenous leukemia. STI-571 also inhibits two type III receptor tyrosine kinases, c-Kit and platelet-derived growth factor receptor, and functions by targeting inactive conformations of these kinases. This review focuses on recent developments in X-ray co-crystal structure analyses of STI-571 bound to Abl and the c-Kit receptor tyrosine kinase domain, and also three other relevant kinase inhibitor co-crystal structures. The similar structural features of these inactive kinases suggest they will be useful for the successful drug discovery and development of specific and targeted gene-based cancer drugs.     

Reinforcement-related brain potentials from medial frontal cortex: origins and functional significance

The development of the field of cognitive neuroscience has inspired a revival of interest in the brain mechanisms involved in the processing of rewards, punishments, and abstract performance feedback. One fruitful line of research in this area was initiated by the report of an electrophysiological brain potential in humans that was differentially sensitive to negative and positive performance feedback [J. Cogn. Neurosci. 9 (1997) 788]. Here we review current knowledge regarding the neural basis and functional significance of this feedback-evoked 'error-related negativity' (ERN). Our review is organized around a set of predictions derived from a recent theory, which holds that the ERN is associated with the arrival of a negative reward prediction error signal in anterior cingulate cortex.