Early deformation mechanisms in the shear affected region underneath a copper sliding contact.

Dislocation mediated plastic deformation decisively influences the friction coefficient and the microstructural changes at many metal sliding interfaces during tribological loading. This work explores the initiation of a tribologically induced microstructure in the vicinity of a copper twin boundary. Two distinct horizontal dislocation traces lines (DTL) are observed in their interaction with the twin boundary beneath the sliding interface. DTL formation seems unaffected by the presence of the twin boundary but the twin boundary acts as an indicator of the occurring deformation mechanisms. Three concurrent elementary processes can be identified: simple shear of the subsurface area in sliding direction, localized shear at the primary DTL and crystal rotation in the layers above and between the DTLs around axes parallel to the transverse direction. Crystal orientation analysis demonstrates a strong compatibility of these proposed processes. Quantitatively separating these different deformation mechanisms is crucial for future predictive modeling of tribological contacts.

Simple 3D images from fossil and recent micromaterial using light microscopy.

Abstract We present a technique for extracting 3D information from small-scale fossil and Recent material and give a summary of other contemporary techniques for 3D methods of investigation. The only hardware needed for the here-presented technique is a microscope that can perform dark field and/or differential interference contrast with a mounted digital camera and a computer. Serial images are taken while the focus is successively shifted from the uppermost end of the specimen to the lowermost end, resulting in about 200 photographs. The data are then processed almost completely automatically by successive use of three freely available programs. Firstly, the stack of images is aligned by the use of CombineZM, which is used to produce a combined image with a high depth of field. Secondly, the aligned images are cropped and sharp edges extracted with the aid of ImageJ. Thirdly, although ImageJ is also capable of producing 3D representations, we preferred to process the image stack further using osirix as it has the facility to export various formats. One of the interesting export formats is a virtual Quicktime movie file (QTVR), which can be used for documentation, and stereo images can also be produced from this Quicktime VR. This method is easy to apply and can be used for documenting specimens in 3D (at least some aspects) without having to prepare them. Therefore, it is particularly useful as a safe method for documenting limited material, before using methods that may destroy the specimen of interest, or to investigate type material that cannot be treated with any preparatory technique. As light microscopes are available in most labs and free computer programs are easily accessible, this method can be readily applied.

Mitosin and pHH3 predict poorer survival in astrocytomas WHO grades II and III.

AIMS: The limitations of the current WHO classification of astrocytomas call for a sustained effort to improve diagnostic and prognostic accuracy. The relationship between tumour growth and clinical outcome suggests that proliferative activity should be examined. The objective of this study was to evaluate the diagnostic and prognostic value of the proliferation markers mitosin and phosphohistone H3 (pHH3) in infiltrative astrocytomas WHO grades II and III and compare the findings with mitotic count and Ki-67/MiB-1 immunostaining. METHODS: Fifty-nine and thirty-three infiltrative astrocytomas WHO grades II and III, respectively, were immunostained with the proliferation markers mitosin and pHH3 using standard immunohistochemical procedures. The expression was quantified as a proliferative index (PI) and statistically evaluated with Spearman's rank correlation test, Wilcoxon-Mann-Whitney U test, and univariable and multivariable COX regression survival analyses. RESULTS: Significant positive correlations were found between these proliferation markers. The number of mitoses, pHH3 mitotic figures (MFs), the Ki-67/MiB-1 PI and the mitosin PI were greater in WHOgrade III anaplastic astrocytomas compared to WHO grade II diffuse astrocytomas, while pHH3 PI only showed a trend. All proliferation markers were associated with poorer prognosis, but mitotic count was not. Ki-67/MiB-1, mitosin and pHH3 MF achieved statistical significance in the univariable analyses of both time to relapse (TTR) and overall survival (OS). Only mitosin remained significant in both multivariable analyses. pHH3 was significant in the multivariable analysis of OS but not of TTR. Clinical factors including age, extent of surgical resection and WHO performance status were also significantly correlated with survival. CONCLUSIONS: In conclusion, mitosin and pHH3 immunostaining have prognostic and diagnostic value in the clinical assessment of patients with infiltrative astrocytomas. The inclusion of proliferation markers in a layered diagnosis should be considered in the upcoming revision of the WHO classification system.

Increased endothelin release by cultured human smooth muscle cells from atherosclerotic coronary arteries.

OBJECTIVES: Endothelin, a 21-amino acid peptide initially purified from the medium of cultured endothelial cells, is a potent vasoconstrictor exerting its effects predominantly in a paracrine or autocrine manner. Recent data indicate that endothelin is also synthesized by cultured vascular smooth muscle cells and that endothelin is an effective stimulator of smooth muscle cell proliferation. This study aimed to investigate the endothelin release of cultured human smooth muscle cells, isolated from coronary plaques and from normal coronary tunica media, and to determine circulating endothelin concentrations in patients with coronary artery disease compared to control subjects. METHODS: Coronary plaque material was extracted by thrombendarterectomy during aorto-coronary bypass grafting (n = 19). Segments of normal coronary arteries were obtained at autopsy (n = 33). Cells were isolated by enzymatic disaggregation and identified as smooth muscle cells with antibodies against smooth muscle alpha-actin. Venous blood samples were drawn from patients with coronary artery disease undergoing cardiac catheterization (n = 32) and from control subjects (n = 38). Endothelin concentrations in culture medium and in plasma samples were measured by radioimmunoassay after Sep Pak C18 extraction. RESULTS: Cultured smooth muscle cells, isolated from coronary plaques, released a significantly (P < 0.001) higher amount of immunoreactive endothelin into the culture medium (39.2 +/- 3.9 pg/10(4) cells, mean +/- s.e.m., 31 supernatant samples) than smooth muscle cells from normal coronary tunica media (3.9 +/- 0.8 pg/10(4) cells, 28 samples). Circulating endothelin concentrations were slightly elevated (P < 0.01) in patients with coronary artery disease (3.8 +/- 0.2 pg/ml) compared to control subjects (3.0 +/- 0.2 pg/ml). CONCLUSIONS: These data suggest that the endothelin production is markedly increased in smooth muscle cells of coronary atherosclerotic plaques. The enhanced endothelin release may stimulate smooth muscle cell proliferation in a paracrine or autocrine manner and thus may contribute to the development or progression of coronary artery disease.

Severe deficiency of 1,25-dihydroxyvitamin D3 in human immunodeficiency virus infection: association with immunological hyperactivity and only minor changes in calcium homeostasis.

The serum level of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D], the biologically most potent metabolite of vitamin D, is tightly regulated within narrow limits in human healthy adults. 1,25-(OH)2D deficiency is rare and is associated with disturbances in calcium and bone metabolism. We have previously reported a marked decrease in serum levels of 1,25-(OH)2D in human immunodeficiency virus (HIV)-infected patients. The present study was designed to further examine the causes and consequences of severe 1,25-(OH)2D deficiency in these patients. The design was a prospective cohort study. Fifty-four HIV-infected patients clinically classified according to the revised criteria from Centers for Disease Control and Prevention and healthy controls were studied. Parameters related to vitamin D and calcium metabolism as well as immunological and nutritional status were determined. Twenty-nine of the patients (54%) had serum levels of 1,25-(OH)2D below the lower reference limit, and 18 of these had undetectable levels. In contrast, HIV-infected patients had normal serum levels of 25-hydroxyvitamin D and vitamin D-binding protein. HIV-infected patients as a group had modestly depressed serum calcium and PTH levels. There were, however, no correlations between these parameters and serum levels of 1,25-(OH)2D. There were no differences in serum calcium or PTH levels or nutritional status when patients with severe 1,25-(OH)2D deficiency were compared to other patients, but patients with undetectable 1,25-(OH)2D had significantly elevated serum phosphate levels. Furthermore, patients with undetectable 1,25-(OH)2D levels were characterized by advanced clinical HIV infection, low CD4+ lymphocyte counts, and high serum levels of tumor necrosis factor-alpha (TNFalpha). We conclude that inadequate 1alpha-hydroxylation of 25-hydroxyvitamin D seems to be the most likely cause of 1,25-(OH)2D deficiency in HIV-infected patients, possibly induced by an inhibitory effect of TNFalpha. The low 1,25-(OH)2D and high TNFalpha levels observed may impair the immune response in HIV-infected patients both independently and in combination and may represent an important feature of the pathogenesis of HIV-related immunodeficiency. Markedly depressed 1,25-(OH)2D serum levels are also present in certain other disorders characterized by immunological hyperactivity. Thus, the findings in the present study may not only represent a previously unrecognized immune-mediated mechanism for induction of 1,25-(OH)2D deficiency in human disease, but may also reflect the importance of adequate serum levels of 1,25-(OH)2D for satisfactory performance of the immune system in man.

Decreased bone formative and enhanced resorptive markers in human immunodeficiency virus infection: indication of normalization of the bone-remodeling process during highly active antiretroviral therapy.

As cytokines and 1,25-dihydroxyvitamin D [1,25-(OH)2D] appear to have an important role in bone homeostasis, we examined the possibility that human immunodeficiency virus (HIV)-infected patients, characterized by enhanced levels of proinflammatory cytokines and 1,25-(OH)2D deficiency, have disturbed bone metabolism by analyzing serum markers of bone formation (osteocalcin) and bone resorption (C-telopeptide) in 73 HIV-infected patients. HIV-infected patients with advanced clinical and immunological disease and high viral load were characterized by increased C-telopeptide and particularly by markedly depressed osteocalcin levels. HIV-infected patients had enhanced activation of the TNF system. Serum concentrations of p55 and p75-TNF receptors were negatively correlated with osteocalcin, and p75-TNF receptor was positively correlated with C-telopeptide. HIV-infected patients with advanced disease also had decreased serum concentrations of 1,25-(OH)2D, but this parameter was not correlated with osteocalcin or C-telopeptide. During 24 months with highly active antiretroviral therapy there was a marked rise in serum osteolcalcin levels together with a profound fall in viral load and TNF components and a marked rise in CD4+ T cell counts. Also, there was a shift from no correlation to a significant correlation between osteocalcin and C-telopeptide levels during such therapy. The present study suggests disturbed bone formation and resorption during HIV infection. Our findings indicating synchronization of bone remodeling during highly active antiretroviral therapy may represent a previously unrecognized beneficial effect of such therapy and expand our knowledge of the interactions between cytokines and bone in the bone-remodeling process.

P-31 nuclear magnetic resonance spectroscopic evaluation of heterotopic cardiac allograft rejection in the rat.

P-31 nuclear magnetic resonance (NMR) spectroscopy was used to evaluate heterotropic cardiac allograft rejection in the rat. To enable optimal application of NMR spectroscopy for the in vivo study of myocardial metabolism in the transplanted organ, an accessory heart transplantation to groin in the rat was used. The allografts were studied in a 1.89 Tesla horizontal bore magnet. Each spectrum was obtained by Fourier transform of 512 scans using 60-degree pulses with 2-sec delays. Changes in phosphocreatine (PCr), adenosine 5-triphosphate (ATP), and inorganic phosphate (Pi) and intracellular pH as determined by P-31 NMR were compared with rejection process as judged by histological studies. Allografts treated with cyclosporine (CsA) did not show any rejection (NR) and had relatively high levels of PCr, and low levels of Pi. Allografts that did not receive any CsA revealed both vascular and cellular rejection. These rejected allografts (R) had relatively low levels of PCr and high levels of Pi. It is concluded that P-31 NMR spectroscopy may have potential application to the clinical diagnosis of cardiac allograft rejection.

31P nuclear magnetic resonance study of renal allograft rejection in the rat.

Phosphorus (31P) nuclear magnetic resonance (NMR) spectroscopy was used to serially evaluate heterotopic renal allograft rejection in the rat. Renal allografts transplanted to the groin of recipient animals were studied using a 1.89 Tesla horizontal bore magnet. The relative intracellular concentrations of phosphorus metabolites such as adenosine triphosphate and inorganic phosphate as well as intracellular pH were determined by 31P NMR on days 4, 7, 10, and 14 following transplantation across a major histocompatibility mismatch. Recipient rats chosen to be rejectors received no immunosuppression while animals chosen to be nonrejectors received cyclosporine during the first 7 days following transplantation. By day 7, all rejector rats could be distinguished from nonrejector rats by their higher relative concentration of inorganic phosphate and their lower relative concentration of adenosine triphosphate. These NMR findings correlated with histologic findings of renal infarction probably related to vascular rejection in the allografts. 31P NMR spectroscopy may have application as a noninvasive tool in the differential diagnosis of posttransplantation renal insufficiency.

Is the transjugular intrahepatic portocaval shunt procedure beneficial for liver transplant recipients?

Recent reports document the efficacy of transjugular intrahepatic portocaval shunts (TIPS) for the prevention of portal hypertensive bleeding and have advocated its use as a bridge to liver transplantation. There are no reports, however, analyzing liver transplant results for patients with indwelling TIPS. We reviewed the records of all adult primary recipients with a history of portal hypertensive bleeding or unmanageable ascites transplanted since the TIPS procedure became available in our institution in July 1991. Seven of 20 recipients underwent TIPS before transplant. There were no significant differences between patients with or without TIPS in age, United Network for Organ Sharing status, Child-Pugh score, preoperative prothrombin time, operative time, operative blood product requirement, overall length of stay, and 6-month patient survival after transplant. We noted a trend toward less operative red cell (26.0 +/- 26.2 vs. 31.8 +/- 38.1 U, mean +/- SD) and autologous blood (4,762 +/- 3,335 vs. 13,355 [corrected] +/- 20,460 ml) transfusion and improved patient survival for those with a TIPS. Patients with a TIPS in place waited significantly longer for their transplant (282 +/- 113 vs. 149 +/- 113 days, P = 0.014). There were 2 technical complications related to the TIPS, 1 in a patient who died after rupture of the suprahepatic vena caval anastomosis where the device had traversed the caval/hepatic vein junction and weakened the tissues, and the other in a survivor in whom the device extended into the right atrium and was extracted during the transplant procedure. Three patients with TIPS in place died of sepsis while waiting for a donor organ. We conclude that while the TIPS offers benefits for the liver transplant recipient, placement of the device in small shrunken cirrhotic livers must be precise. Immediate benefits for the transplant candidate may be offset by increased waiting time and technical complications at the transplant operation.

Liver transplantation for primary hepatic cancer.

Although early survival following transplantation for primary hepatic cancer is excellent, previously reported high recurrence rates have generally discouraged liver replacement for this indication. Since the inception of the Boston Center for Liver Transplantation (BCLT) in 1983, 33 of 383 (8.6%) liver allograft recipients have undergone orthotopic transplantation as definitive treatment for otherwise unresectable cancer. Diagnoses included hepatocellular carcinoma (HCCA) in 24 patients (73%), and cholangiocarcinoma (CHCA) in 9 patients (27%). Actuarial survival rates for patients with hepatocellular carcinoma were 71%, 56%, and 42% at 1, 2, and 3 years, respectively. The actuarial survival rates for patients with cholangiocarcinoma were 89% at 6 months, and 56% at 1, 2, and 3 years. Of the nine patients with cholangiocarcinoma, 56% (5/9) developed recurrent disease. Although this recurrence rate is disheartening, because of the lack of other morbidity, long-term survival in these patients is comparable to patients with HCCA. In contrast, recurrent hepatocellular carcinoma developed in 25% of recipients (5/20) who survived longer than 3 months posttransplantation. Other causes of death in patients with hepatocellular carcinoma included perioperative complications, 16.6% (4/24); sepsis, 8.3% (2/24); coronary artery disease, 4.2% (1/24); and lymphoma, 4.2% (1/24). Favorable prognostic factors included: primary tumor less than 3 cm in size and absence of associated cirrhosis. These results emphasize that orthotopic liver transplantation can provide a long-term cure for approximately 50% of patients whose primary hepatic malignancy is unresectable by conventional procedures.

A phase I trial of immunosuppression with anti-ICAM-1 (CD54) mAb in renal allograft recipients.

Several adhesion molecules contribute to the interaction between T cells and antigen presenting cells or target cells. Leukocyte function-associated molecule-1 (LFA-1[CD11a/CD18]) and intercellular adhesion molecule-1 (ICAM-1 [CD54]) are one such critical adhesive receptor-counter-receptor combination. The importance of ICAM-1 dependent adhesion in the rejection response was initially demonstrated in cynomolgus renal allograft recipients treated with the anti-ICAM-1 murine monoclonal antibody BIRR1. BIRR1 also appeared to limit ischemic damage in these animals. A Phase I clinical trial has subsequently been completed in 18 patients who received cadaver donor renal allografts at high risk for delayed graft function (prolonged preservation time, highly-sensitized recipient). An adequate BIRR1 serum level was associated with significantly less delayed graft function (P < .01) and rejection (P < .01). In 1-hr biopsies, mouse IgG was detected along the endothelium of the vessels and glomeruli in the graft. There were no instances of primary non-function (PNF), and current allograft survival (followup: 16-30 months) in these "high-risk" mAb-treated patients is 78%. There were 3 instances of PNF and a graft survival rate of 56% in the recipients of the contralateral kidney allografts treated with conventional immunosuppression. No significant "first-dose" effect was associated with BIRR1 administration. These results establish a dosing schedule and the clinical safety of BIRR1. They also suggest that inhibition of leukocyte adhesion by mAb therapy may be useful in controlling allograft rejection and possibly in limiting reperfusion injury. Thus, these observations support the clinical importance of accessory molecules in T cell function. We hypothesize that anti-CD54 mAb acts by blocking leukocyte adhesion to the endothelium, thereby interfering with sensitization or target cell interaction.

Different effect of 1,25-dihydroxyvitamin D3 on replication of Mycobacterium avium in monocyte-derived macrophages from human immunodeficiency virus-infected subjects and healthy controls.

Mycobacterium avium complex (MAC) is the most common cause of disseminated bacterial infection in patients with acquired immune deficiency syndrome (AIDS) and macrophage dysfunction is important both in the pathogenesis of AIDS- and MAC-infection. 1,25-Dihydroxyvitamin D3 (1,25D), the active metabolite of vitamin D, has a number of effects on cell types of the immune system including monocytes/macrophages. The present study was designed to investigate whether 1,25D supplementation in vitro could modulate MAC replication in macrophages from HIV-infected patients. It was therefore of particular interest to examine whether the effect of 1,25D differs between cells from HIV-infected patients and healthy control subjects. After 3 and 7 days of infection, 1,25D supplementation increased numbers of bacteria in cells from control subjects. In contrast, there was no change or even a decrease in numbers of bacteria in cells from HIV-infected patients. These findings suggest that HIV infection may significantly modulate the macrophage response to 1,25D stimulation, and that 1,25D may have inhibitory effects on MAC replication in macrophages from HIV-infected patients.

The effect of 1,25-vitamin D3 on maturation of monocytes from HIV-infected patients varies with degree of immunodeficiency.

The active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D), has been shown to induce monocyte-to-macrophage maturation in vitro as well as monocytic differentiation of bone marrow precursors and monocytic leukaemic cell lines. In this study we assessed whether 1,25D could improve the maturation defect we have previously demonstrated in monocytes from AIDS patients. In vitro growth and maturation of monocytes from 10 controls, 15 asymptomatic HIV positives (CDC group II or III) and 13 symptomatic HIV positives (CDC group IV) was examined by assessing cellular morphology, differentiation, adherence and protein content. Cells were cultured for 10 days with or without addition of 1,25D at a concentration of 100 pg/ml. In addition, patients were monitored clinically and by immunological parameters and HIV p24 antigen in serum. The present study showed that addition of 1,25D significantly improved the growth and maturation in both patient and control groups. There was a significant negative correlation between response to 1,25D and CD4+ lymphocyte count in blood in HIV-infected patients. A greater response to 1,25D was seen in monocytes from patients with advanced immunodeficiency and symptomatic disease than in monocytes from asymptomatic patients. However, in the most advanced cases of HIV infection with serious ongoing opportunistic infections the response to 1,25D was very poor, possibly reflecting profound and incorrigible dysfunction of monocytes.

Elevated plasma endothelin concentrations in cyclosporine-treated patients after bone marrow transplantation.

Administration of cyclosporine is often associated with the development of renal dysfunction and hypertension. Since recent data from animal experiments provide evidence that endothelin, a potent vasoconstrictive peptide, might play a role in mediating cyclosporine-related renal and cardiovascular side-effects, the present study was designed to investigate whether plasma endothelin concentrations are elevated in cyclosporine-treated patients. Plasma endothelin concentrations, determined by radioimmunoassay after Sep Pak C18 extraction, were significantly elevated in cyclosporine-treated patients after bone marrow transplantation (8.3 +/- 1.4 ng/l, n = 28) compared to patients not treated with cyclosporine after bone marrow transplantation (3.9 +/- 0.2* ng/l, n - 11), patients with haematological disorders (3.9 +/- 0.3** ng/l, n = 11) not treated with bone marrow transplantation and to normal control subjects (3.1 +/- 0.2*** ng/l, n = 33) (*P < 0.05, **P < 0.01, ***P < 0.001). Furthermore, plasma endothelin levels exhibited a significant correlation with cyclosporine concentrations (r = 0.57, P < 0.01). The present data, demonstrating elevated plasma endothelin concentrations in cyclosporine-treated patients, suggest that the cyclosporine-associated renal and cardiovascular side-effects might in part be mediated by cyclosporine-induced stimulation of endothelin release.

A new microvascular model for noninvasive nuclear magnetic resonance spectroscopy of the transplanted kidney.

The cellular biology of graft rejection is not well understood. Phosphorus-31 nuclear magnetic resonance (31P NMR) spectroscopy is a new noninvasive technique for the measurement of intracellular pH and relative amounts of phosphorus-containing compounds, such as adenosine triphosphate (ATP), inorganic phosphate, phosphocreatine, and sugar phosphates, in any tissue from which a clear signal can be obtained. Biochemical analysis of such precision, without the need for tissue destruction, represents an unusual opportunity for analysis of in vivo cellular metabolism under varying conditions, including graft rejection. 31P NMR study of intra-abdominal viscera has not been feasible in most laboratories without laparotomy because of signal interference from abdominal wall muscle. In this study, to eliminate this interference, a rat kidney was transplanted to the groin, where it could be serially studied without overlying skeletal muscle. This new vascular technique was successful in 11 of 11 attempts and maintained normal serum creatinines in 10 chronic survivors after removal of both native kidneys. The 31P NMR spectroscopic signal from the groin kidney is clear and highly reproducible. This new microvascular model will make it possible to carry out noninvasive long-term spectroscopic studies that could potentially identify a reliable marker for allograft rejection.

A novel method for continuous online glucose monitoring in humans: the comparative microdialysis technique.

The aim of this study was to prove the feasibility of continuous subcutaneous glucose monitoring in humans using the comparative microdialysis technique (CMT). The performance of the CMT was determined by comparing tissue glucose values with venous or capillary blood glucose values in healthy volunteers and type 1 diabetic subjects. The CMT is a microdialysis-based system for continuous online glucose monitoring in humans. This technique does not require calibration by the patient. Physiological saline with glucose (5.5 mM) is pumped in a stop-flow mode through a microdialysis probe inserted into the abdominal s.c. tissue. Tissue glucose concentration is calculated by comparing the dialysate and perfusate glucose concentrations. The time delay due to the measurement process is 9 min. We tested the CMT on six healthy volunteers and six type 1 diabetic patients for 24 h in our clinical setting. Comparisons were made to HemoCue analyzer (Angelholm, Sweden) capillary blood glucose measurements (healthy volunteers) and to venous blood glucose concentration determined with a Hitachi analyzer (diabetic patients). The mean absolute relative error of the CMT glucose values from the blood glucose values was 17.8+/-15.5% (n = 167) for the healthy volunteers and 11.0+/-10.8% (n = 425) for the diabetic patients. The mean difference was 0.42+/-1.06 mM (healthy volunteers) and -0.17+/-1.22 mM (diabetic patients). Error grid analysis for the values obtained in diabetic patients demonstrated that 99% of CMT glucose values were within clinically acceptable regions (regions A and B of the Clarke Error Grid). The study results show that the CMT is an accurate technique for continuous online glucose monitoring.

Serum angiotensin-converting enzyme activity and active renin plasma concentrations in insulin-dependent diabetes mellitus.

We report here the alterations of serum angiotensin-converting enzyme activity (S-ACE) and of active renin plasma concentrations (ARPC) in 41 insulin-dependent diabetes mellitus (IDDM) patients compared with those of 26 control subjects. The IDDM patients had S-ACE activity (54 +/- 16 I.E.) in the upper normal range (controls, 39 +/- 7). When the patients were subclassified according to their diabetic complications, a significant increase of S-ACE within the IDDM group compared to the controls was observed in patients with nephropathy (68 +/- 13, P less than 0.001) with persistent proteinuria and with retinopathy (63 +/- 14, P less than 0.001). A significant correlation was found between proteinuria and S-ACE (r = 0.98, P less than 0.001) and between retinopathy and S-ACE levels (r = 64, P less than 0.001). No correlation between blood pressure and S-ACE or between blood glucose and S-ACE was observed. The ARPC were within the normal range in the IDDM (21 +/- 9 ng/l) and in control (19 +/- 3) groups. No correlations between ARPC and blood pressure or blood glucose or the degree of diabetic complications were registered. These data show that S-ACE activity is elevated in IDDM patients with nephropathy-proteinuria and/or with retinopathy and the circulating renin may not represent the renal renin-angiotensin vascular system.

Recent advances in continuous glucose monitoring.

Continuous glucose monitoring, providing more detailed information on glucose excursions than single spot measurements, should help to improve the therapy in diabetic patients and is also required for feedback-controlled insulin delivery. At the Institute for Diabetes-Technology in Ulm, founded by EF Pfeiffer, a portable glucose sensor for continuous tissue glucose monitoring has been developed. The combination of microdialysis and enzymatic amperometric glucose measurement implemented in this device marked a break-through in achieving reliable and precise continuous tissue glucose monitoring. In several studies, we have demonstrated that continuous subcutaneous glucose monitoring for up to 72 hours is feasible under 'in-house' and 'daily life' conditions in diabetic patients. The measured tissue glucose concentrations correlated closely to glucose control measurements in venous and capillary blood. A reliable continuous glucose monitoring device is a prerequisite for the development of an artificial pancreas. Our group developed an algorithm for subcutaneous application of the fast acting insulin analogon lispro. In experiments performed over 7 and 24 hours good metabolic control was achieved by algorithm-based insulin application. In addition, the algorithm was able to maintain acceptable metabolic control during and after moderate physical exercise. Further work is needed to optimize continuous tissue glucose monitoring systems and to develop a closed loop system for insulin application based on continuously measured tissue glucose concentrations.

Plasma brain natriuretic peptide and atrial natriuretic peptide concentrations correlate with left ventricular end-diastolic pressure.

The present study was designed to investigate whether brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) plasma concentrations correlate with left ventricular end-diastolic pressure (LVEDP), pulmonary capillary wedge pressure (PCWP), diastolic pulmonary arterial pressure (DPAP), right atrial pressure (RAP), or ejection fraction (EF). Plasma BNP and ANP levels were determined by commercial radioimmunoassays (Peninsula) after Sep Pak C18 extraction in blood samples withdrawn from the pulmonary artery and the left ventricle or from the left ventricle and the femoral vein in 85 patients undergoing diagnostic cardiac catheterization. Linear and nonlinear regression analysis and the paired sample t-test were applied to the data. Pulmonary arterial plasma BNP and ANP levels showed a close nonlinear correlation with LVEDP (BNP: r = 0.94, p < 0.001; ANP: r = 0.81, p < 0.001), a significant linear correlation with PCWP, DPAP, and RAP, and a significant negative correlation with EF. ANP concentrations decreased significantly from the pulmonary artery to the left ventricle and from the left ventricle to the femoral vein (p < 0.001). BNP levels also decreased significantly between the left ventricle and the femoral vein (p < 0.001), but there was no significant difference between pulmonary arterial and left ventricular BNP concentrations. BNP and ANP concentrations correlated significantly between pulmonary arterial and left ventricular blood samples (BNP: r = 0.99, ANP: r = 0.93, p < 0.001) and between left ventricular and peripheral blood samples (BNP: r = 0.99, ANP: r = 0.94, p < 0.001). The present data suggest that peripheral plasma BNP and ANP levels are useful non-invasive indices of cardiac performance.