Pharmacokinetics and pharmacodynamics of the non-nucleoside reverse-transcriptase inhibitor etravirine in treatment-experienced HIV-1-infected patients.

The pharmacokinetics and pharmacodynamics of the antiretroviral agent etravirine were evaluated in two phase III clinical trials. Pharmacokinetic data were available in 577 patients randomized to receive etravirine. The mean (SD) population-pharmacokinetics-derived area under the concentration-time curve at 12 h (AUC(12 h)) and concentration at 0 h (C(0 h)) were 5,501 (4,544) ng·h/ml and 393 (378) ng/ml, respectively. Hepatitis C coinfection raised etravarine exposure, and concomitant use of tenofovir disoproxil fumarate lowered etravirine exposure, but these changes were not considered clinically relevant. Etravirine apparent oral clearance was not affected by age, weight, sex, race, hepatitis B coinfection status, creatinine clearance, or concomitant use of enfuvirtide. Virologic response (<50 copies/ml) at week 24 was 59% in patients randomized to etravirine vs. 41% in those receiving placebo (P < 0.0001). There was no apparent relationship between etravirine pharmacokinetics and either efficacy or safety. Factors other than the pharmacokinetics of etravirine such as the characteristics of the patients and the disease, as well as characteristics of the treatment regimen, predict virologic response.

Device-specific outcomes after endovascular abdominal aortic aneurysm repair.

Over the last decade, endovascular aneurysm repair (EVAR) has been used extensively for the elective treatment of infra-renal abdominal aneurysms. However, it remains unclear how specific devices perform and how they compare to others. We provide an overview of currently used endografts, and discuss the current evidence regarding device-specific outcomes. Published literature confirms differences in results according to endograft selection. These differences were more pronounced with older generations of devices, in comparison to newer models. Contemporary results are generally good and one should remember that no randomized data exist regarding individual device performance. Moreover, by the time there is enough follow-up to draw conclusions, the data is relatively obsolete due to constant improvements in endograft technology and design. Results from EVAR have been steadily improving and individualized device selection has shown to be valuable. It appears that patients with favorable anatomy do well with most modern endografts. Those with challenging anatomies may benefit more from a particular design, delivery and deployment feature requiring greater knowledge and experience for adequate device selection.

Assessment of the steady-state pharmacokinetic interaction between etravirine administered as two different formulations and tenofovir disoproxil fumarate in healthy volunteers.

OBJECTIVE: Two open-label, randomized, cross-over trials in healthy volunteers were conducted to investigate the pharmacokinetic interaction between etravirine and tenofovir disoproxil fumarate. METHODS: Etravirine was administered as either 800 mg twice a day (bid) (phase II formulation in Study 1) or 200 mg bid (phase III formulation in Study 2) for 8 days followed by a 12 h pharmacokinetic evaluation. After a minimum of 14 days washout, tenofovir disoproxil fumarate 300 mg once a day was administered for 16 days. Volunteers were randomized to receive co-administration of etravirine with tenofovir disoproxil fumarate on either days 1-8 or days 9-16 followed by a 12 h pharmacokinetic evaluation for etravirine on day 8 or 16, respectively. Plasma and urine tenofovir concentrations were determined on days 8 and 16 over 24 h. RESULTS: The least square mean (LSM) ratio [90% confidence interval (CI)] for the area under the plasma concentration-time curve from 0 to 12 h (AUC(12 h)) for etravirine co-administered with tenofovir disoproxil fumarate vs. etravirine alone was 0.69 (0.61-0.79) and 0.81 (0.75-0.88) in Studies 1 and 2, respectively. The LSM ratio (90% CI) for the effect of etravirine on tenofovir AUC(24 h) was 1.16 (1.09-1.23) in Study 1 and 1.15 (1.09-1.21) in Study 2. CONCLUSIONS: These alterations are not considered clinically relevant for either drug and no dose adjustment is necessary when etravirine and tenofovir disoproxil fumarate are co-administered.

Endovascular treatment of traumatic ruptures of the thoracic aorta.

Rupture of the thoracic aorta after a blunt traumatic accident is a life-threatening event. This injury is instantly fatal in about 80% of the victims, and half of those who initially survive the incident will die during the first day, if left untreated. Before 1997, patients were treated with an open repair, but the conventional surgical approach carries a high mortality and morbidity rate. Graft interposition and cross-clamping of the aorta are responsible for a high paraplegia rate. Despite the fact that active distal perfusion of the aorta lowers the incidence of neurological deficit, the timing of these extensive procedures in the severely injured multi-trauma patient is difficult. The endovascular repair of a traumatic thoracic aortic rupture has gained rapid acceptance as a better alternative. This minimally invasive procedure has a median operating time of <1 h, and it can be done during the same session in which other life-threatening injuries are repaired. There is no need for a thoracotomy or single lung ventilation, blood loss is minimal and systemic heparinization is not required. So far, no spinal cord ischemia has been described for the endovascular repair. Besides numerous advantages, a few problems can be expected. The narrow aortic diameter of these young trauma-victims, combined with a steep aortic arch, makes the adaptation of the endograft along the inner curvature sometimes difficult. Because the smallest endograft usually exceeds the narrow aortic diameter, only excessively oversized devices can be used, which explains the high type I endoleak encountered in the published series. No randomized studies are yet available comparing the open with the endovascular technique, but the initial results of the endovascular repair seem promising and lower mortality and morbidity rates are documented. Long-term outcome are lacking so far, but are needed to address the durability of the procedure. Further research and development should concentrate on the problems we have seen with steep and narrow aortic arches, and devices with more flexible curves and smaller diameters should become available in the near future.

[Evaluation of the rate of autopsy and rate of disparity between autopsy results and clinical cause of death in a surgical ward, with the emphasis on necrological review]. / Een onderzoek naar het percentage obducties en naar discrepanties tussen obductiebevindingen en klinische doodsoorzaak op een heelkundige afdeling met extra aandacht voor necrologiebesprekingen.

OBJECTIVE: To determine the rate of autopsy and the rate of disparity between autopsy results and the clinically determined cause of death in a surgical ward. DESIGN: Descriptive. METHOD: A total of 12,000 patients were admitted to the surgical ward of the Red Cross Hospital, the Hague, the Netherlands, from January 1999 to December 2002. 305 (3%) died during their stay on the ward. By using our standard mortality registration system, it was possible to classify the causes of death, evaluate shortcomings in treatment, and determine the extent of agreement between pre- and post-mortem findings. RESULTS: Permission for an autopsy was obtained for 136 patients (45%). The autopsy rates in patients who died following abdominal aortic surgery, colonic surgery, peripheral artery bypass surgery, and hip surgery were 55%, 63%, 35% and 30%, respectively. In 37 patients (27%), the autopsy report revealed a disparity with the clinical cause of death. Patients who died after abdominal aortic surgery or colonic surgery had disparity rates of 33% and 21%, respectively. Patients who died after peripheral artery bypass surgery or hip surgery had disparity rates of 13% and 7%, respectively. CONCLUSION: The overall rate of autopsy was lower (45%) than in the period 1992-1998 (60%), but remained relatively high in patient groups who were previously found to have a high rate of disparity between pre- and post-mortem findings. Post-mortem examination remains an important tool that can be used to verify diagnosis and treatment and therefore assess the quality of care.

Contemporary series of morbidity and mortality after lower limb amputation.

OBJECTIVES: This study was performed in order to assess morbidity and mortality associated with major lower extremity amputation according to an extensive complication registration system used in our hospital. METHODS: All consecutive patients who underwent lower limb major extremity amputation were included from January 1996 until December 2002. Complications were prospectively registered according to our standard complication registration system. RESULTS: In 97 patients 122 amputations were performed including 45 above (AKA) and 77 below (BKA) knee amputations. The conversion rate from below to above knee amputation was 14%. In 65 patients 107 complications occurred (67%). The incidence of wound infection was 10% in the BKA group and 2% in the AKA group. The most frequently reported complications were pressure sores (8%) or originating from the urinary tract (13%). The hospital mortality for BKA was 9% and for AKA 18%. Long-term survival was 62% at 1 year, 50% at 2 years and 29% at 5 years. CONCLUSIONS: An extensive registration system provides us with a detailed insight into the incidence, consequence and cause of complications. Major lower extremity amputations are still associated with considerable morbidity and mortality.

Wound drainage versus non-drainage for proximal femoral fractures. A prospective randomised study.

OBJECTIVES: The purpose of this prospective randomised study was to examine whether routine drainage in surgery for traumatic hip fractures is useful. BASIC PROCEDURES: At the end of surgery for hip fractures, 200 consecutive patients (51 men, 149 women) were randomised to receive suction drainage or not. The status of wound healing was evaluated, with specific reference to haematoma formation or wound infection. Indices of blood loss were the average blood loss during operation, a decrease in the haemoglobin level, fluid collected by the drain, and blood transfusion. MAIN FINDINGS: The severity of wound haematoma and the number of wound infections was not significantly different between the two groups. The average blood loss during operation was 172 ml in the drainage group and 179 ml in the non-drainage group. The volume of drainage fluid was 146 ml. The haemoglobin concentration decreased by 1.4 mg/dl in the drainage group and by 1.3 mg/dl in the non-drainage group (P = 0.83). During admission, 55 patients in the drainage group received 2.5 units of blood and 50 patients in the non-drainage group received 2.7 units. CONCLUSIONS: The severity of wound haematoma does not lead to statistically significant differences in wound infection rate. The routine use of suction drains may not prevent wound infections.

Mortality after colon surgery: the value of a mortality registration system.

BACKGROUND/AIMS: Postoperative mortality after colon surgery is relatively infrequent. In order to evaluate the quality of colon surgery, post-mortem evaluation is useful. This study was performed to determine the value of a mortality register used at the Department of Surgery of the Red Cross Hospital. METHODS: From 1991 to 2000, 882 colon resections were performed for both malignant and benign disorders, including elective and emergency surgery. Permission for autopsy was asked routinely. All cases were reviewed and categorized in a multidisciplinary meeting. Any discrepancy between the clinical and post-mortem diagnosis was determined by a pathologist. RESULTS: The mortality rate of colon surgery was 8.0% (n = 71), 23% for emergency surgery and 6% for elective surgery (p < 0.001). For patients under 70 years of age the mortality rate was 4.3%, for patients over 70 years of age 11.2% (p < 0.001). Autopsy was performed in 62% (n = 44) of the patients. Discrepancy between clinical and post-mortem findings was documented in 14%. CONCLUSION: Postoperative mortality after colon surgery is influenced by the timing of surgery (elective or emergency procedure) and the age of the patient. A discrepancy of 14% between clinical cause of death and post-mortem cause of death justifies the need for obtaining autopsy in this type of surgery.

Complication registration in patients after peripheral arterial bypass surgery.

The objective of this study was to describe the kinds of complications and their incidence after peripheral vascular surgery of the lower limb, coding for causes and effect on the patient. In this prospective study, a standardized complication registration system was used at the Red Cross Hospital, The Hague. All patients (n = 373) receiving an infrainguinal bypass graft during the period January 1, 1996 to December 31, 1999 were included. All postoperative complications occurring during admission were coded. In 29% of the patients 153 complications were coded. Early occlusions of the graft occurred 36 times, wound infections 21 times and postoperative hemorrhages 20 times. Postoperative retention of urine was seen most frequently of all nonspecific complications (n = 22). In 43 cases the patient needed medication or a blood transfusion for his complication. In 42 cases a re-intervention was necessary. Complications led to a prolonged stay in the hospital in 20 cases. Six patients died during admittance (mortality 1.6%). An error in surgical therapy and error in nonsurgical therapy were the cause of the complication in 108 cases (out of 153). The advantage of this complication registration is that it describes all complications, not just the specific ones. Furthermore, by categorizing all complications we force ourselves to look for errors in nonsurgical therapy and surgical technique and to describe the effect of the complication.

Epicardial outgrowth inhibition leads to compensatory mesothelial outflow tract collar and abnormal cardiac septation and coronary formation.

In the present study, we investigated the modulatory role of the epicardium in myocardial and coronary development. Epicardial cell tracing experiments have shown that epicardium-derived cells are the source of interstitial myocardial fibroblasts, cushion mesenchyme, and smooth muscle cells. Epicardial outgrowth inhibition studies show abnormalities of the compact myocardial layer, myocardialization of cushion tissue, looping, septation, and coronary vascular formation. Lack of epicardial spreading is partly compensated by mesothelial outgrowth over the conotruncal region. Heterospecific epicardial transplant is able to partially rescue the myocardial development, as well as septation and coronary formation.

Smooth muscle cells and fibroblasts of the coronary arteries derive from epithelial-mesenchymal transformation of the epicardium.

Previous research has revealed that cells contributing to coronary vascular formation are derived from the dorsal mesocardium, however, the fate of these cells during consecutive stages of heart development is still unclear. We have conducted a study regarding the recruitment of vascular components and the subsequent differentiation into mature vessel wall structures with the aid of immunohistochemical markers directed against endothelium, smooth muscle cells, and fibroblasts. The proepicardial organ including an adhering piece of primordial liver of quail embryos (ranging from HH15 to HH18) was transplanted into the pericardial cavity of chicken embryos (ranging from HH15 to HH18). The chicken-quail chimeras (n=16) were harvested from the early stage of endothelial tube formation (HH25) to the late stage of mature vessel wall composition (HH43). Before HH32 endothelial cells have invaded the myocardium to give rise to yet undifferentiated coronary vessels. These endothelial cells are not accompanied by other non-endothelial cells. The superficial epicardial layer changes from a squamous mesothelium into a cuboid epithelium preceding media and adventitia formation. Subsequently, a condensed area of mesenchymal cells delaminates from the cuboidal lining extending toward the vessel plexus. Around the coronary arteries, these mesenchymal cells differentiate into smooth muscle cells or fibroblasts as shown by immunohistochemical markers. We conclude that epithelial-mesenchymal transformation of the epicardial lining delivers the smooth muscle cells and fibroblasts of the coronary arterial vessel wall. Molecules involved in epithelial transformation processes elsewhere in the embryo are also expressed within the subepicardial layer, and are considered to participate in inducing this process.

The value of a mortality-scoring system in the quality control of patients undergoing abdominal aortic surgery.

OBJECTIVES: to assess the quality of care of patients undergoing abdominal aortic surgery. MATERIALS: three hundred and forty-six patients undergoing surgery for aneurysmal or occlusive disease of whom 51 died. METHODS: we developed a mortality registration system to classify causes of death, to evaluate shortcomings in treatment, and to determine the extent of agreement between clinical diagnosis and necropsy findings. RESULTS: the main cause of death for 11 patients (22%) was a poor clinical condition at admission, while 76% (n=39) of the patients died due to postoperative complications. Myocardial infarction was the most frequently encountered complication. Deficiencies in medical treatment were observed in 10 of the 51 deaths (20%). Autopsy was performed in 33 of the 51 patients (65%), revealing in 10 cases (30%) a major discrepancy between pre- and postmortem findings. Six of the 10 autopsies revealed that a myocardial infarction had been missed during the postoperative period. CONCLUSIONS: autopsy reports are essential for accurately estimating complication rates as we observed discrepancies in 30% of cases.

Epicardium-derived cells contribute a novel population to the myocardial wall and the atrioventricular cushions.

The epicardium and dorsal mesocardium are known to be the source of structures that form the wall of the coronary vessels. Because mouse knockout studies have shown that proper epicardial formation is also essential for myocardial development, we have studied in detail the migration and differentiation of epicardium-derived cells (EPDCs) within the developing heart. We constructed chicken-quail chimeras by grafting the quail epicardial organ, including a piece of primordial liver, at essentially stages 16 and 17. The embryos were studied at stages 25 to 43. To detect quail-derived EPDCs, an anti-quail nucleus antibody was used in combination with several differentiation markers, eg, for muscle actin, for vascular smooth muscle cells, for procollagen-I, for quail endothelium, and for Purkinje fibers. At stages 25 to 31, EPDCs are encountered in the myocardial wall and the subendocardial region. The latter deposition is spatially facilitated as the endocardium protrudes through transient discontinuities in the myocardium to contact the subepicardial layer. Later on, at stages 32 to 43, EPDCs invaded, by way of the atrioventricular sulcus, the atrioventricular cushion tissue. The localization is apparent at the interface with the myocardium, as well as subendocardially, but never within the endocardial lining. The origin of endothelium, smooth muscle cells, and fibroblasts of the coronary vessel wall from the epicardial graft were confirmed in accordance with already published data. The functional role of the novel EPDCs in the subendocardium, myocardium, and atrioventricular cushions remains to be investigated. A close positional relationship is found with the differentiating Purkinje fibers. Furthermore, a regulatory role is postulated in the process of endocardial-mesenchymal transformation. The ultimate fate of EPDCs seems to be a cardiac fibroblast cell line involved in the formation of the fibrous heart skeleton.

The development of the coronary vessels and their differentiation into arteries and veins in the embryonic quail heart.

Research concerning the embryologic development of the coronary plexus has enriched our understanding of anomalous coronary vessel patterning. However, the differentiation of the coronary vessel plexus into arteries, veins, and a capillary network is still incomplete. Immunohistochemical techniques have been used for whole mounts and serial sections of quail embryo hearts to demonstrate endothelium, vascular smooth muscle cells, and fibroblasts. From HH35 onward, the lumen of the coronary plexus was visualized by injecting India ink into the aorta. In HH17, branches from the sinus venosus plexus expand into the proepicardial organ to reach the dorsal side of the atrioventricular sulcus. From HH25 onward, vessel formation proceeds toward the ventral side and the apex of the heart. After lumenized connections of the coronary vessels with the aorta and right atrium are established, a media composed of smooth muscle cells and an adventitia composed of procollagen-producing fibroblasts are formed around the coronary arteries. In the early stage, bloodflow through the coronary plexus is possible, although connections with the aorta have yet to be established. After the coronary plexus and the aorta and right atrium are interconnected, coronary vessel differentiation proceeds by media and adventitia formation around the proximal coronary arteries. At the same time, the remodeling of the vascular plexus is manifested by disappearance of arteriovenous anastomoses, leaving only capillaries to connect the arterial and venous system.

Relative exercise intensity of long-distance marching (120 km in 4 days) in 153 subjects aged 69-87 years.

The aim of this study was to determine the relative exercise intensity (oxygen uptake during the march/maximal oxygen uptake, VO2march/VO2max) during a long-distance march in subjects or over 70 years of age. Secondly, the effect of hypertension, cardiovascular and pulmonary diseases on the relative exercise intensity was evaluated. One hundred and fifty-three subjects, 97 men aged 76.7 (4.6) years and 56 women aged 72.8 (3.6) years who completed the 1993 Nijmegen day long-distance march (30 km x day(-1) on 4 consecutive days) participated in the study. Oxygen uptake (VO2) during walking at different velocities (v) was measured in a subgroup of nine men and nine women, selected randomly from the population under study. With these data, regression equations describing the relationship between VO2 and v were made. VO2march was estimated with the obtained regression equations from an average of the v(march) measured in all participants. VO2max was determined using incremental cycle ergometry in all subjects. VO2march was 13.7 (1.8) ml x kg(-1) x min(-1) in men and 15.2 (1.3) ml x kg x min(-1) in women at a mean v of 5 km x h(-1) in both sexes. This corresponded to 52% of VO2max in men and 63% in women. In both sexes subjects with cardiovascular and/or pulmonary diseases walked at a slower v and thus lower VO2march compared to subjects without these diseases. Due to the lower VO2max in subjects with these diseases there was no difference in the relative exercise intensity between the groups. A multiple linear regression analysis showed that and not age on the prevalence of hypertension, cardiovascular and/or pulmonary that VO2max was the most important predictor of the variance in self-selected v(march). This study demonstrates that these active people aged over 70 years could maintain a high relative exercise intensity during endurance walking on 4 subsequent days. Furthermore, it shows that the relative exercise intensity of marching is within the range recommended for improving fitness and reducing the risk of cardiovascular diseases. Finally, these results demonstrate that VO2max has a more important influence on performance than does age or chronic diseases in active elderly people.

A 27Al MAS, MQMAS and off-resonance nutation NMR study of aluminium containing silica-based sol-gel materials.

Aluminium containing hybrid materials were prepared via the sol-gel method using aluminium sec-butoxide complexed with ethylacetoacetate (Al(OBus)2EAA or Al(OBus)3/EAA mixtures). As silanes, phenyltrimethoxysilane (PhTMS) or phenyltriethoxysilane (PhTES), 3-glycidoxypropyl trimethoxysilane (Glymo) and tetraethylorthosilicate (TEOS) were used. After room temperature drying of the samples the 27Al single pulse excitation (SPE) magic angle spinning (MAS) NMR shows that octahedral (5 ppm) and tetrahedral (55 ppm) coordinated aluminium species are present in the materials. The relative amount of these two species depends on the preparation method. However, the Al(IV)/Al(VI) ratio is lower than 3 (typically 2.3) in all materials, indicating the presence of a small amount of an aluminate phase. Annealing of the samples at 100, 150 and 200 degrees C results in the formation of an extra signal at 30 ppm (peak maximum measured at 11.7 T). Based on the resonance frequency this signal is generally assigned to a pentahedrally coordinated aluminium species. Hydration/dehydration processes of annealed samples were studied with 27Al SPE MAS NMR, multiple-quantum MAS NMR (MQMAS) and off-resonance nutation NMR. Upon hydration of the annealed sample the signal intensity around 30 ppm decreases in intensity and at the same time the intensity of the signal around 55 ppm increases by the same amount (tetrahedrally coordinated aluminium). The MQMAS spectra reveal that the signal around 30 ppm is not caused by a fivefold-coordinated aluminium species but mainly by tetrahedrally coordinated aluminium species in a distorted environment, experiencing large quadrupole induced shifts and small chemical shifts due to conformational changes in the polymeric network. From the MQMAS NMR spectra it can be concluded that the linebroadening observed in the 27Al MAS NMR spectra is due to both a distribution in isotropic chemical shifts and a distribution in quadrupole coupling constants (Cqcc = e2qQ/h). Hydration of the sample results in a decrease of the average Cqcc for the tetrahedrally coordinated aluminium from 6 to 4 MHz, whereas the average Cqcc of the octahedrally coordinated aluminium is hardly influenced (4 MHz). These MQMAS results are confirmed by off-resonance nutation experiments.

Differences in development of coronary arteries and veins.

OBJECTIVE: The differentiation of the coronary vasculature was studied to establish in particular the formation of the coronary venous system. METHODS: Antibody markers were used to demonstrate endothelial, smooth muscle, and fibroblastic cells in serial sections of embryonic quail hearts. The anti-beta myosin heavy chain and the neuronal marker HNK-1 were added to our incubation protocol. RESULTS: In HH32, the coronary vascular network has developed into a circulatory system with connections to the sinus venosus, the aorta and the right atrium. The connections between the aorta and the right atrium allow for direct arteriovenous shunting. Subsequently, differentiation into coronary arteries and veins occurs with an interposed capillary network. The smooth muscle cells of the coronary arterial media derive from the subepicardial layer, whereas the subepicardially located cardiac veins recrute atrial myocardium, as these cells express the beta-myosin heavy chain antigen. Ganglia are located in the subepicardium close to the vessels, while nerve fibres tend to colocalize with the formed vessel channels. CONCLUSIONS: A new finding is presented in which the subepicardial coronary veins have a media that consists of myocardial cells. The close positional relationship of neural tissue and coronary vessels that penetrate the heart wall is explained as inductive for vessel wall differentiation, but not for invasion into the heart.

Cytokeratins as a marker for epicardial formation in the quail embryo.

Several techniques have been used to visualize the migration pattern of the epicardial cells from the proepicardial organ over the myocardial surface. As the epicardial cells contain keratin tonofilament bundles, we have incubated 92 whole-mount quail hearts with an anti-keratin antibody. This immunohistochemical method showed that the complete epicardial covering of the embryonic heart is preceded by the formation of three epicardial rings. The epicardial rings are formed on the outer myocardial surface in the grooves that separate the cardiac segments from each other. We have also documented timing and patterning of isolated epicardial islands. They are not encountered at random over the myocardial surface, but only along the edge of the advancing epicardial front border and in two defined future epicardial ring areas on the ventral side of the outflow tract. The epicardial islands suggest that in the quail free-floating parts of epicardium can attach to the myocardium. Characteristics of the surface of the myocardium at the transitional zones between the cardiac segments, as well as the three-dimensional remodelling of the heart during cardiac morphogenesis seem to play a role in the pattern in which the epicardium eventually completely ensheaths the myocardial surface. Congenital heart defects are often related to malpositioned transitional zones that dictate the pattern of epicardial outgrowth. As the embryonic position of the epicardial rings is mirrored in the pattern of the main arterial stems, the coronary vascularization pattern might be altered in congenitally malformed hearts as well.