Surgical treatment of abdominal compression syndromes: The significance of hypermobility-related disorders.

Case reports and systematic studies of the most common hypermobility-related disorders, hypermobile Ehlers-Danlos syndrome (hEDS), and hypermobility spectrum disorder (HSD) typically describe gastroenterological symptoms and complaints attributed to structural malfunction, autonomic dysfunction, or inflammation of the gastrointestinal tract. However, abdominal compression syndromes (CS) may also contribute to pain and dysfunction in these individuals and be the leading pathology given symptoms significantly reduce or cease after decompressive surgery. Arising not only in the abdomen and causing pain (median arcuate ligament syndrome [MALS] and superior mesenteric artery syndrome [SMAS]), CS also occur in the retroperitoneum and the pelvis (nutcracker syndrome and May-Thurner syndrome), these latter conditions causing chronic pelvic congestion syndrome (PCS). Here, we report primarily on our experience of the assessment and management of MALS and SMAS in a cohort of cases with a surprising prevalence of HSD and hEDS. To our knowledge, this is the first cohort report of its kind in hEDS, HSD, and CS. We recommend that CS are considered in hEDS and HSD individuals with gastrointestinal and other painful complaints within the "belt" area. These CS can be identified using functional ultrasound duplex examination in experienced hands, and in appropriate cases stabilizing surgery can substantially improve quality of life.

Interprofessional Management of Median Arcuate Ligament Syndrome (Dunbar Syndrome) Related to Lumbar Lordosis and Hip Dysplasia: A Patient's Perspective.

We present a 53-year-old female patient with median arcuate ligament syndrome (MALS), also known as Dunbar syndrome or celiac artery compression syndrome, related to lumbar lordosis and hip dysplasia. She utilized interprofessional management strategies, which were beneficial in reducing lumbar lordosis and MALS-related symptoms. This finding is important because there are no other reports in the literature describing interprofessional strategies to manage symptoms for patients who are waiting for surgery or are not candidates for surgery. LEARNING POINTS: Excessive lumbar lordosis is related to the development of median arcuate ligament syndrome (MALS) due to the greater distance the median arcuate ligament stretches around the vertebral curves, causing compression of the celiac nerves and artery.It is important to consider the effects MALS has on multiple body systems when diagnosing and developing symptom management strategies.Referrals to interprofessional team members can help the patient manage the vast array of symptoms related to MALS.

Venous blood flow in maternal kidneys in third trimester of pregnancy.

Objectives: Maternal intra-abdominal pressure and hemodynamics change during pregnancy. The left renal vein may be compressed between the uterus and the spine and aorta, causing congestion and impaired venous return from the left kidney during late pregnancy. The aim of this study was to compare venous and arterial blood flow between the right and left kidney in the third trimester in women without known pregnancy complications.Methods: We conducted a prospective cohort study in 50 women with uncomplicated third-trimester pregnancies at Trondheim University Hospital, Norway, from January to April 2018. The arterial and venous blood flow were examined with pulsed wave Doppler in the hilum of the kidneys and the cross section of the area (CSA) of the vessels was measured from 3D acquisitions. Two diameters of the main vein and artery were measured after rotating the image of the vessels in the C-plane to be as circular as possible. CSA was calculated as π×(mean diameter/2)2. Blood flow volume (ml/minute) in the vessels were calculated as 0.5 × TAmax (cm/s)×CSA (cm2)×60. The main outcome was venous and arterial blood flow volumes, and secondary outcomes were maximum velocity (Vmax), minimum velocity (Vmin), pulsatile index (PI), time-averaged maximum flow (TAmax) and renal interolobar vein impedance index (RIVI). We also examined possible associations between blood flow and maternal age, BMI and blood pressure.Results: We observed differences in venous flow parameters between the two kidneys. The mean total flow volume in the renal veins was 274 ml/min in the left vein versus 358 ml/min in the right vein (p=.10). Vmax, TAmax, PI, and RIVI were all significantly lower in the left renal vein. No differences in arterial blood flow between the two kidneys were found. BMI was negatively correlated to flow in the left renal vein (r= -0.28; p<.05), but not associated to flow in the right renal vein.Conclusion: We found that venous flow pattern differs between left and right renal veins in uncomplicated late pregnancies, but the total flow was not significantly different. New studies should be done in women with preeclampsia.

Correlation Between Fetal Weight Gain and Birth Weight with Blood Flow in the Uterine Arteries Calculated with the PixelFlux Technique.

INTRODUCTION: The aim was to investigate correlations between fetal weight gain/day and birthweight with blood flow estimates in the uterine arteries calculated with the PixelFlux technique and with measurements from TAmax. We also aimed to examine the agreement between estimates using the two methods. MATERIAL AND METHODS: We conducted a prospective observational pilot study in pregnancy week 24-25 in women with risk pregnancies referred to the fetal medical centre at St. Olavs Hospital, Trondheim, Norway from March 2016 to June 2016. Blood flow in the uterine arteries was calculated using time-averaged peak velocity (TAmax) and the PixelFlux technique. PixelFlux is a method based on pixelwise calculation of spatially angle-corrected velocities and areas of all pixels inside a vessel during a heart cycle. RESULTS: The mean flow calculated from PixelFlux and TAmax was 811 ml/minute and 787 ml/minute, respectively. The intra-class correlation coefficient was 0.83 (95% CI 0.72-0.90) and limits of agreement were -441 ml/minute (95% CI -558 to -324 ml/minute) to 489 ml/minute (95% CI 372 to 606 ml/minute). We observed a significant correlation between mean flow calculated from PixelFlux and birthweight (r=0.41; p<0.01) and between flow calculated from PixelFlux and weight gain/day (r=0.33; p=0.02). Calculation based on TAmax was significant correlated to birthweight (r=0.34; p=0.02), but not to weight-gain/day. Pulsatile index was not correlated to flow, birthweight or fetal weight-gain/day. CONCLUSIONS: We found significant correlations between estimated blood flow in the uterine arteries using the PixelFlux technique with fetal weight-gain/day and with birthweight. Estimates from two methods showed good agreement.

Color Doppler dynamic tissue perfusion measurement: a novel tool in the assessment of renal parenchymal perfusion in children with vesicoureteral reflux.

INTRODUCTION: Vesicoureteral reflux (VUR) occurs in 20-50% of children suffering from recurrent urinary tract infections (UTIs) and is associated with an increased risk of renal scarring and impaired renal function. Early detection of renal perfusion deterioration would allow for the implementation of more aggressive treatment and potentially prevent further damage to the renal parenchyma. The aim of the study was to assess renal parenchymal perfusions in children with recurrent UTIs with and without coexisting VUR, and compare the findings with the results of healthy patients. MATERIAL AND METHODS: Color Doppler sonographic dynamic renal parenchymal perfusion measurements were performed with PixelFlux (Chameleon-Software, Germany) software in 77 children with recurrent UTIs and coexisting VUR and in 30 children with UTIs without VUR. The findings were compared with the results of 53 healthy children. RESULTS: Cortical parenchymal perfusion of children suffering from UTIs and VUR was significantly reduced when compared to the control group. Statistically significant differences (p < 0.05) were found in all perfusion parameters (i.e. mean velocity (v mix ), mean perfused area (A mix ), mean perfusion intensity (I mix ), tissue pulsatility index (TPI), and tissue resistance index (TRI)) between the control group and children suffering from UTIs and VUR, particularly VUR grades III and IV. There were no significant differences between the UTI group and the control group. No differences were found between the controls and VUR grade II. CONCLUSIONS: Renal parenchymal perfusion decreases significantly with higher grades of VUR.

Laparoscopic treatment of celiac artery compression syndrome in children and adolescents.

BACKGROUND: The celiac artery compression syndrome (CACS) is a rarely diagnosed disorder, which is characterized by chronic abdominal pain and vegetative symptoms. The role of surgical treatment in celiac artery decompression has been discussed controversially by numerous authors. After first casuistic descriptions of a laparoscopic treatment in adults we established this novel minimally invasive procedure for treatment in children and adolescents. PATIENTS AND METHODS: Between 2005 and 2014 we operated 58 patients (47 female, 11 male) from 7 to 25 years who had been diagnosed with celiac artery compression. The patients presented with severe chronic abdominal pain, vegetative symptoms and a reduced quality of life. Doppler sonography showed an increased blood flow velocity of the celiac artery with maximum of 190 - 450 cm/s (mean 259 cm/s).MR angiography demonstrated a characteristic hook-shaped appearance of the celiac artery with severe localized compression. RESULTS: All patients underwent laparoscopic decompression of the celiac artery. We observed complications in 3 patients (5,2 %). Postoperatively all patients (100 %) were immediately free of abdominal pain. Doppler sonography showed a marked reduction in celiac blood flow velocity to 70 - 190 cm/s postoperatively (mean 178 cm/s). A return of vessel diameters to normal dimensions was documented by postoperative MR angiography. During a median follow up of 62 months we observed a recurrence of the celiac artery compression in 4 patients (6,9 %). CONCLUSIONS: Laparoscopic treatment of celiac artery compression syndrome offers a novel, safe, reliable and, compared to open surgery, less invasive approach. The surgical treatment is indicated in patients with characteristic symptoms and typical findings at Doppler sonography and MRA after exclusion of other abdominal pathologies. The work-up of chronic abdominal pain in children and adolescents should include a color Doppler sonography to look for celiac artery compression.

Correlation of histopathologic and dynamic tissue perfusion measurement findings in transplanted kidneys.

BACKGROUND: Cortical perfusion of the renal transplant can be non-invasively assessed by color Doppler ultrasonography. We performed the Dynamic Tissue Perfusion Measurement (DTPM) of the transplant's renal cortex using color Doppler ultrasonography (PixelFlux technique), and compared the results with the histopathological findings of transplant biopsies. METHODS: Ninety-six DTPM studies of the renal transplant's cortex followed by transplant biopsies were performed in 78 patients. The cortical perfusion data were compared with the parameter of peritubular inflammatory cell accumulation (PTC 0 to 3) based on Banff-classification system. RESULTS: A significant decrease of cortical perfusion could be demonstrated as the inflammatory cells accumulation in peritubular capillaries increased. Increasing peritubulitis caused a perfusion loss from central to distal layers of 79% in PTC 0, of 85% in PTC 1, of 94% in PTC 2, and of 94% in PTC 3. Furthermore, the perfusion loss due to peritubular inflammation was more prominent in the distal cortical layer. The extent of perfusion decline with increasing peritubulitis (from PTC 0 to PTC 3) was 64% in proximal 20% cortical layer (p20), 63% in proximal 50% cortical layer (p50), increased to 76% in distal 50% cortical layer (d50), and peaked at 90% in the distal 20% cortical layer (d20). For those without peritubulitis (PTC 0), the increase in the the Interstitial Fibrosis/Tubular Atrophy (IF/TA) score was accompanied by a significantly increased cortical perfusion. A Polyomavirus infection was associated with an increased cortical perfusion. CONCLUSIONS: Our study demonstrated that the perfusion of the renal transplant is associated with certain pathological changes within the graft. DTPM showed a significant reduction of cortical perfusion in the transplant renal cortex related to peritubular capillary inflammation.

Dynamic tissue perfusion measurement: a new tool for characterizing renal perfusion in renal cell carcinoma patients.

INTRODUCTION: Renal cell carcinoma (RCC) is characterized by intense angiogenesis with hyperexpression of proangiogenic factors. This study explored the potential of dynamic tissue perfusion measurement (DTPM) to detect differences in tissue perfusion between kidneys with RCC and corresponding healthy kidneys. PATIENTS AND METHODS: 30 patients with unilateral, histologically confirmed RCC underwent DTPM by color Doppler ultrasound. Before scheduled surgery, Doppler ultrasound data were acquired from four transverse areas of the affected kidney and the contralateral healthy kidney. Doppler ultrasound data were recorded over a 10-second period and characteristic tissue perfusion parameters were determined. RESULTS: The kidneys with RCC displayed characteristic changes in perfusion parameters. A significant increase in signal intensity and a significant decrease in flow resistance were noted. A combination of several DTPM parameters was used to distinguish correctly between kidneys bearing RCC or healthy kidneys with up to 75% accuracy. There was no association between the perfusion parameters and the pathological characteristics of the respective tumors. CONCLUSIONS: DTPM is a promising tool for the evaluation of whole-organ tissue perfusion. This study demonstrates the feasibility of performing DTPM measurements in kidneys bearing RCC lesions. In tumors that are characterized by extensive neovascularization, this method has the potential to be a valuable diagnostic tool.

pO polarography, contrast enhanced color duplex sonography (CDS), [18F] fluoromisonidazole and [18F] fluorodeoxyglucose positron emission tomography: validated methods for the evaluation of therapy-relevant tumor oxygenation or only bricks in the puzzle of tumor hypoxia?

BACKGROUND: The present study was conducted to analyze the value of ([18F] fluoromisonidazole (FMISO) and [18F]-2-fluoro-2'-deoxyglucose (FDG) PET as well as color pixel density (CPD) and tumor perfusion (TP) assessed by color duplex sonography (CDS) for determination of therapeutic relevant hypoxia. As a standard for measuring tissue oxygenation in human tumors, the invasive, computerized polarographic needle electrode system (pO2 histography) was used for comparing the different non invasive measurements. METHODS: Until now a total of 38 Patients with malignancies of the head and neck were examined. Tumor tissue pO2 was measured using a pO2-histograph. The needle electrode was placed CT-controlled in the tumor without general or local anesthesia. To assess the biological and clinical relevance of oxygenation measurement, the relative frequency of pO2 readings, with values < or = 2.5, < or = 5.0 and < or = 10.0 mmHg, as well as mean and median pO2 were stated. FMISO PET consisted of one static scan of the relevant region, performed 120 min after intravenous administration. FMISO tumor to muscle ratios (FMISOT/M) and tumor to blood ratios (FMISOT/B) were calculated. FDG PET of the lymph node metastases was performed 71 +/- 17 min after intravenous administration. To visualize as many vessels as possible by CDS, a contrast enhancer (Levovist, Schering Corp., Germany) was administered. Color pixel density (CPD) was defined as the ratio of colored to grey pixels in a region of interest. From CDS signals two parameters were extracted: color hue--defining velocity (v) and color area--defining perfused area (A). Signal intensity as a measure of tissue perfusion (TP) was quantified as follows: TP = vmean x Amean. RESULTS: In order to investigate the degree of linear association, we calculated the Pearson correlation coefficient. Slight (|r| > 0.4) to moderate (|r| > 0.6) correlation was found between the parameters of pO2 polarography (pO2 readings with values < or = 2.5, < or = 5.0 and < or = 10.0 mmHg, as well as median pO2), CPD and FMISOT/M. Only a slight correlation between TP and the fraction of pO2 values < or = 10.0 mmHg, median and mean pO2 could be detected. After exclusion of four outliers the absolute values of the Pearson correlation coefficients increased clearly. There was no relevant association between mean or maximum FDG uptake and the different polarographic- as well as the CDS parameters. CONCLUSION: CDS and FMISO PET represent different approaches for estimation of therapy relevant tumor hypoxia. Each of these approaches is methodologically limited, making evaluation of clinical potential in prospective studies necessary.

From the nutcracker-phenomenon of the left renal vein to the midline congestion syndrome as a cause of migraine, headache, back and abdominal pain and functional disorders of pelvic organs.

This paper presents the hypothesis, that pain and functional disturbances of organs which lie on the midline of the body might be caused by a venous congestion of these organs. Cause of their congestion is the participation of these organs (vertebral column, skull, brain, spinal medullary, uterus, prostate, left ovary/testis, urinary bladder rectum, vagina, urethra) in the collateral circulation of the left renal vein. In many patients with complaints of the above mentioned organs the left renal vein is compressed inside the fork formed by the superior mesenteric artery and the aorta. This so called nutcracker phenomenon is incompletely understood today. It can lead to a marked reduction of left renal perfusion and forces the left renal blood to bypass the venous compression site via abundant collaterals. These collaterals are often not sufficient. Their walls become stretched and distorted - varices with inflamed walls are formed. These dilated veins are painful, interfere with the normal organ's function and demand more space than usual. This way pain in the midline organs and functional derangement of the midline organs can occur. The term "midline congestion syndrome" seems appropriate to reflect the comprehensive nature of this frequent disorder. The rationale for this hypothesis is based on the novel PixelFlux-technique (www.chameleon-software.de) of renal tissue perfusion measurement. With this method a relevant decline of left renal cortical perfusion was measured in 16 affected patients before therapy (left/right ratio: 0.79). After a treatment with acetylsalicylic acid in doses from 15 to 200mg/d within 14-200 days a complete relief of so far long lasting therapy-resistant midline organ symptoms was achieved. Simultaneously the left/right renal perfusion ratio increased significantly to 1.24 (p=0.021). This improvement of left renal perfusion can be explained by a better drainage of collateral veins, diminution of their wall distension, thereby decline of their intramural inflammation, reduction of their mass effects (especially by the replaced spinal fluid inside the spinal canal and the skull), and altogether a reduction of pain and functional derangement in the affected midline organs. The proposed theory might influence the current understanding of such frequent and difficult to treat diseases as chronic back pain, headaches, frequent cystitis, enuresis, abdominal pain, flank pain and might spur new theories of arterial hypertension, placental insufficiency, prostate diseases and myelopathies.

Tissue pulsatility index: a new parameter to evaluate renal transplant perfusion.

BACKGROUND: : Chronic allograft nephropathy (CAN) is characterized by loss of parenchymal perfusion. We applied therefore the novel parameter Tissue Pulsatility Index (TPI) to quantify transplant perfusion in the long-term surveillance of renal transplants. METHODS: : Color Doppler sonographic videos of renal transplants from 38 renal transplant recipients were recorded under defined conditions. TPI was calculated as ratio of the difference of mean systolic and diastolic velocities of the entire region and the average velocity. RESULTS: : TPI was significantly different between the proximal and distal cortical layers (1.12 vs. 1.56, respectively P=0.000). In patients with elevated creatinine as a measure of compromised function, significantly (P=0.016) higher values (TPI=1.70) were found at distal cortical level compared to patients with normal creatinine (TPI=1.34). After transplantation, TPI rises significantly: 1.10 in 0-1 years vs. 1.41 in 1-2.9 years, P=0.002; 1.10 in 0-1 years vs. 1.37 in 3-4.9 years, P=0.000; 1.10 in 0-1 years vs. 1.31 in 7-8.9 years, P=0.049). TPI declines later on in our population to significantly lowered values in the group more than 9 years after transplantation (1.10 in 0-1 years vs. 0.94 in >9 years, P=0.044). CONCLUSION: : With the novel TPI, we could demonstrate significant differences between proximal and distal cortical perfusion, between compromised and well-functioning transplants, and could observe significant changes of transplant perfusion at various points at the posttransplantation time scale.

Celiac artery compression syndrome in children, adolescents, and young adults: clinical and color duplex sonographic features in a series of 59 cases.

OBJECTIVE: Abdominal pain is one of the most common conditions in childhood and adolescence. Celiac artery compression syndrome (CACS) is rarely suspected in this population. We present clinical and sonographic features from a series of 59 patients with this disorder. METHODS: A total of 3449 patients from 0 to 18 years were investigated with 7639 abdominal color duplex sonographic examinations. Celiac artery flow velocity was measured at the branching off from the aorta in inspiration, expiration, and in between. Diagnosis of CACS was made if a greater than 2-fold acceleration of peak systolic flow in the celiac artery compared to the abdominal aorta or a peak systolic velocity greater than 200 cm/s was measured in the mid position and if a variation of flow velocity occurred during respiration. In 22 cases, angiography (21 magnetic resonance angiography and 1 digital subtraction angiography) was used to prove sonographic diagnosis. RESULTS: Fifty-nine patients (among them 81% female) from 22 months to 19 years (clustering between 14 and 17 years) fulfilling color Doppler sonographic criteria of CACS were found, for a prevalence of 1.7%. Their symptoms included, among others, abdominal pain (71%), nausea (29%), thoracic pain (22%), heartburn (17%), weight loss (15%), vomiting (15%), systolic murmur (15%), postprandial accentuation of symptoms (15%), diarrhea (14%), respiratory discomfort (14%), and syncope (12%). CONCLUSIONS: Celiac artery compression syndrome is more prevalent than expected, and conditions not usually connected to the disease were found. Alertness to CACS is recommended, especially in patients with a combination of characteristic symptoms. Color Doppler sonography is the modality of choice for diagnosing CACS.

Dynamic tissue perfusion measurement: a novel tool in follow-up of renal transplants.

BACKGROUND: The authors applied the novel method of noninvasive dynamic color Doppler sonographic parenchymal perfusion measurement to renal transplants. METHODS: Color Doppler sonographic videos of renal transplants from 38 renal transplant recipients were recorded under defined conditions. Specific tissue perfusion was calculated as mean flow velocity encoded by color Doppler signals of a region of interest during one full heart cycle. RESULTS: The authors could demonstrate significant differences of central versus peripheral cortical perfusion intensity (1.36 vs. 0.60 cm/sec) and a significant loss of perfusion intensity in the posttransplantation period in the peripheral cortex from 1.06 cm/sec in the first year to a minimum of 0.39 cm/sec in the 3- to 5-year interval, with stronger perfusion in longer surviving transplants: 0.71 cm/sec more than 9 years after transplantation. In the central cortex, a similar but less pronounced pattern could be demonstrated. A significant drop of parenchymal perfusion was found in patients with elevated serum creatinine (1.36 cm/sec in cases with normal and 0.82 cm/sec in those with elevated creatinine at the proximal cortical level). The perfusion ratio of the central 50% and the peripheral 50% shows marked changes over time: in the first year, the ratio was 2.99, climbing to 5.56 at the 3- to 5-year interval and declining later on. CONCLUSIONS: Cortical tissue perfusion in renal transplants was quantified noninvasively from color Doppler signal data in an easily accomplishable manner. Renal transplants showed a marked decline in tissue perfusion after transplantation. Perfusion is significantly lower in transplant function loss with elevated serum creatinine.

New method of dynamic color doppler signal quantification in metastatic lymph nodes compared to direct polarographic measurements of tissue oxygenation.

Tumor growth depends on sufficient blood and oxygen supply. Hypoxia stimulates neovascularization and is a known cause for radio- and chemoresistance. The objective of this study was to investigate the use of a novel ultrasound technique for the dynamic assessment of vascularization and oxygenation in metastatic lymph nodes. Twenty-four patients (age 44-78 years) with cervical lymph node metastases of squamous cell head and neck cancer were investigated by color duplex sonography and 17 (age 46-78 years) were investigated additionally with polarography. Sonography was performed after contrast enhancer infusion under defined conditions. Intranodal perfusion data (color hue, colored area) were measured automatically by a novel software technique. This allows an evaluation of blood flow dynamics by calculating perfusion intensity--velocity, perfused area, as well as the novel parameters tissue resistance index (TRI) and tissue pulsatility index (TPI)--for each point of a complete heart cycle. Tumor tissue pO(2) was measured by means of polarographic needle electrodes placed intranodally. The sonographic and polarographic data were correlated using Pearson's test. Sonography demonstrated a statistically significant inverse correlation between hypoxia and perfusion and significant TPI and TRI changes with different N-stages. The percentage of nodal fraction with less than 10 mmHg oxygen saturation was significantly inversely correlated with lymph node perfusion (r = -0.551; p = 0.021). Nodes with a perfusion of less than 0.05 cm/sec flow velocity showed significantly larger hypoxic areas (p = 0.006). Significant differences of TPI and TRI existed between nodes in stage N(1) and N(2)/N(3) (p = 0.028 and 0.048, respectively). This new method of dynamic signal quantification allows a noninvasive and quantitative assessment of tumor and metastatic lymph node perfusion by means of commonly available ultrasound equipment.

A new method of color Doppler perfusion measurement via dynamic sonographic signal quantification in renal parenchyma.

OBJECTIVE: Perfusion quantification of tissues is an important goal to evaluate the state of blood supply of an organ. We developed a method to quantify tissue perfusion via color Doppler signal quantification from sonographic videos and applied this to describe renal parenchymal perfusion in healthy kidneys. METHOD: Color Doppler sonographic videos of renal perfusion from both kidneys of 87 healthy children (age 2 weeks to 16 years) were recorded under defined conditions. Perfusion data (color hue, color area) were measured in a standardized region of interest automatically. Signal intensity was calculated as whole ROIs (regions of interest) mean flow velocity (cm/s) encoded by color Doppler signals during one full heart cycle. RESULTS: Normal signal intensity values are: 1.86 cm/s in the region encompassing central 50% of the renal cortex and 0.56 cm/s in the peripheral 50% of the renal cortex. These differences are significant. Signal intensity of both kidneys did not differ. CONCLUSION: Signal intensity of cortical tissue in healthy kidneys was quantified noninvasively from color Doppler signal data in an easily accomplishable manner with new measurement software. Normal values for this technique have been calculated. Possible further applications might be all situations, where perfusion changes could be expected like inflammation, renal insufficiency, vascular diseases and tumors.