In type 2 diabetic patients, cardiac events in the perioperative period may be associated with diminished myocardial vasomotor function and endothelial dysfunction. The influence of sevoflurane anaesthesia on myocardial endothelial dysfunction in type 2 diabetic mellitus is investigated in this pilot study.Six males with type 2 diabetes mellitus and eight healthy controls were included. Using myocardial contrast echocardiography, myocardial blood flow (MBF) was measured at rest, during adenosine-induced hyperaemia (endothelium-independent vasodilation) and after sympathetic stimulation by the cold pressor test (endothelium-dependent vasodilation). Measurements were performed before and after induction of sevoflurane anaesthesia.Sevoflurane anaesthesia decreased resting MBF in diabetics but not in controls (P = 0.03), while baseline MBF did not differ between diabetics and controls. Without anaesthesia, adenosine-induced hyperaemia increased MBF in both groups compared to resting values. Adenosine combined with sevoflurane resulted in a lower hyperaemic MBF in both groups compared to no anaesthesia. Differences in MBF in response to adenosine before and after sevoflurane administration were larger in diabetic patients, however not statistically significant in this pilot group (P = 0.08). Myocardial blood flow parameters after the cold pressor test were not different between groups.These pilot data in type 2 diabetic patients show that sevoflurane anaesthesia decreases resting myocardial blood flow compared to healthy controls. Further, we observed a trend towards a lower endothelium-independent vasodilation capacity in diabetic patients under sevoflurane anaesthesia. Endothelium-dependent vasodilation was not affected by sevoflurane in diabetic patients. These data provide preliminary insight into myocardial responses in type 2 diabetic patients under general anaesthesia.http://www.clinicialtrials.gov,NCT00866801 Diabetes mellitus is a major risk factor for cardiovascular morbidity and mortality. In the Myocardial endothelial function can be evaluated by measuring vasodilator responses to sympathetic stimulation (primarily endothelium-dependent vasodilation) and to vascular smooth muscle relaxing agents, such as adenosine and dipyridamole (primarily endothelium-independent vasodilation). Studies in humans with type 2 diabetes have shown attenuation of myocardial responses to adenosine and dipyridamole-10. AlsoSevoflurane is a frequently used volatile anaesthetic with coronary vasodilating properties,12. ExpeWe hypothesised that myocardial endothelial function is affected by general anaesthesia in patients with type 2 diabetes mellitus. This pilot study was undertaken to investigate how type 2 diabetic patients respond to myocardial vasodilators under sevoflurane anaesthesia when compared to healthy controls.et al.[The local Human Subjects Ethics Committee of the VU University Medical Center in Amsterdam, the Netherlands, approved this study (ID 2008/304). Subsequent patients were included after written informed consent. We prospectively studied 6 patients with type 2 (non-insulin dependent) diabetes mellitus and 8 healthy control subjects, all scheduled for non-cardiac surgery under general anaesthesia. Six out of 8 healthy volunteers were selected based on sex from a previously published study by Bulte et al.. The diaAll participants made an extra visit to our hospital for screening, autonomic function testing and baseline myocardial blood flow measurements. On the day of surgery the MBF measurements were repeated after the induction of sevoflurane anaesthesia but before the start of the surgical procedure.-1 min-1 adenosine. Finally, sympathetic stimulation was triggered by the cold pressor test (CPT) by immersing the hand of the patient in ice water (2 – 4°C) for 3 minutes. Perfusion sequences were recorded and consisted of 10 cardiac cycles of low acoustic power  imaging for microbubble detection followed by a burst of high acoustic power (MI 0.64) for microbubble destruction. Subsequently, 20 cardiac cycles were recorded with low MI imaging at a frame rate of 18 Hz to allow contrast replenishment in the myocardium. All data were stored for offline analysis.As previously described, transthoracic myocardial contrast echocardiography (MCE) was performed using an iE33 ultrasound scanner equipped with a S5 – 1 transducer . A contrAll subjects underwent a set of standard autonomic function tests to screen for cardiovascular autonomic neuropathy. First, subjects are placed in the supine position and heart rate  was recorded for 5 min during spontaneous breathing. Subsequently, autonomically induced variations in R – R intervals to changes in blood pressure were recorded during one minute of deep breathing, during the Valsalva manoeuvre  and quick stand test. R – R intervals and blood pressure were continuously recorded using a non-invasive continuous finger arterial blood pressure measurement device with a sample rate of 200 Hz . Data was stored on a personal computer for further analysis using free available software . During spontaneous breathing over 5 minutes, heart rate variability (HRV) was assessed by spectral analysis using fast Fourier transformation. This method divides the overall variability of a signal into its composing frequencies and provides insight into what extent a frequency contributes to the overall variability. The power spectrum of HRV consists of three peaks: the very-low-frequency band (<0.04 Hz), the low-frequency band (0.04 – 0.12 Hz) and the high-frequency band (0.12 – 0.40 Hz). The very-low-frequency fluctuations mediated primarily by the sympathetic system, the low-frequency fluctuations by both the sympathetic and parasympathetic system and the high-frequency fluctuations are under parasympathetic control.From the recordings during deep breathing, maximum and minimum R – R intervals were extracted and expressed as a ratio, which in healthy subjects should be larger than 1.17. For the Valsalva manoeuvre, subjects exhaled forcibly through a manometer against a pressure of 40 mmHg for 15 s. The ratio of R – R intervals was calculated, being > 1.21 in healthy subjects. Assessment of heart rate response during quick standing, R – R intervals were measured at 15 and 30 beats after standing. In healthy subjects, the ratio of the longest R – R interval to the shortest R – R interval is > 1.04. To assess changes in blood pressure during standing, systolic blood pressure was measured in the resting, supine subject. Two minutes after rapid standing, the measurement was repeated. In healthy subjects the fall in systolic blood pressure after the test should be less than 10 mmHg. Cardiac autonomic neuropathy is defined as the presence of 3 or more abnormal test results among these 7 tests.-1 intravenously. Anaesthesia was induced by sevoflurane inhalation  and maintained at an age-adjusted end-tidal concentration of 1.0 minimum alveolar concentration. A laryngeal mask airway was inserted and patients continued to breathe spontaneously without positive airway pressure during the study period. The surgical procedure started after MBF measurements were completed.Heart rate, blood pressure and oxygen saturation were monitored throughout the protocol. All patients received midazolam 0.02 mg kget al., myocardial blood flow was quantified in ml min-1 g-1 from the underlying microvascular parameters: (1) the relative myocardial blood volume, which represents the blood volume in the capillary system, and (2) the capillary exchange rate, which provides an estimate of the exchange rate of erythrocytes within the region of interest[Semiautomated software providing manual region of interest (ROI) tracking, visualisation of perfusion calculations and dataset handling was used . ROIs were drawn in end-systolic frames in the mid-inferoseptal and mid-anterolateral wall ; in the mid-inferior and mid-anterior wall  and in the mid-inferolateral and mid-anteroseptal wall  of the myocardium. Using the volumetric model by Vogel interest. ChangesAll data are presented as mean ± SD unless indicated otherwise. Baseline characteristics between controls and diabetics were compared using a Mann–Whitney U test. A Wilcoxon signed-rank test was used for within group comparisons of myocardial blood flow results (baseline versus sevoflurane). Changes in myocardial blood flow responses before and during sevoflurane administration were compared between controls and diabetics using a Mann–Whitney U test. Descriptive statistics were provided for hemodynamic data. A P < 0.05 was considered as statistically significant.Table Clinical assessment of autonomic function in the control group revealed no abnormal responses to the tests Table . In the At baseline, heart rate and RPP increased in both groups during adenosine infusion Table . These rSevoflurane anaesthesia decreased MBF in diabetics but not in controls (P = 0.03). At baseline, adenosine-induced hyperaemia increased MBF in both groups compared to resting values. However, when adenosine was combined with sevoflurane anaesthesia, the MBF was significantly lower in both controls and diabetics when compared to baseline conditions Figure . DiffereIn this pilot study, we show that sevoflurane anaesthesia impairs resting myocardial blood flow in type 2 diabetic patients, while it preserves myocardial blood flow in healthy controls. Furthermore, we observed a decrease in hyperaemic MBF (endothelium-independent vasodilation) during sevoflurane anaesthesia in both groups, with a trend towards a larger decrease in diabetic patients. Sympathetic stimulation under sevoflurane did not lead to changes in MBF in controls or diabetics when compared to baseline (endothelium-dependent vasodilation). These findings suggest different myocardial responses to sevoflurane anaesthesia in type 2 diabetic patients compared to healthy controls.et al. showed that diabetic coronary dysfunction is clinically characterised by increased basal MBF and similar hyperaemic MBF compared to healthy patients[et al. reported similar resting MBF and lower hyperaemic MBF in diabetics compared to controls[et al. reported no difference in resting MBF in streptozotocin-induced type 1 diabetic rats compared to controls rats under thiopental anaesthesia[Type 2 diabetes mellitus leads to endothelial dysfunction of the coronary circulation due to reduced availability of nitric oxide, accumulation of glycation end products in the arterial wall, impaired insulin signalling, inflammation and other still unknown mechanisms,21. Piccpatients. In contcontrols. The addesthesia. No studet al., showing higher hyperaemic MBF in controls than in diabetic rats, confirm the latter observation[Sevoflurane anaesthesia decreased MBF during adenosine-induced hyperaemia in both groups when compared to baseline conditions. This was in accordance with our previous study in healthy volunteers. Also, dervation. Underlyervation.Endothelial-dependent vasodilation by the CPT during sevoflurane anaesthesia was not different from baseline in both controls and diabetic patients. It has been shown that the MBF response to sympathetic stimulation is primarily dependent on the integrity of the autonomic nervous system and not on hemodynamic changes or circulating catecholamine levels. Also, iFor this study sevoflurane anaesthesia was used since it is widely available and allows both induction and maintenance of anaesthesia. Volatile anaesthetics are thought to possess cardioprotective properties although experimental evidence suggests that these properties are reduced in type 2 diabetes. InteresAll type 2 diabetic patients in this study received oral antidiabetic therapy (see Table The small number of patients studied limits interpretation of the present study results. However, pilot studies are valuable and necessary to enable power calculation for future studies. Ideally, in subsequent studies age-matched controls should be used for comparison with diabetic subjects. The age difference between healthy controls and diabetic subjects in this study could be a potential confounder.Already in this small study population we showed that sevoflurane reduces resting MBF in diabetic patients compared to healthy controls. Hyperaemic MBF decreased during sevoflurane anaesthesia in both groups. Next, an adequately powered study should be undertaken; for hyperaemia a sample size of 21 in each group will have 80% power to detect a significant difference using a two-group t-test with a 0.05 two-sided significance level. For cold pressor testing, a sample size of 92 in each group will have 80% power to detect a significant difference using a two-group t-test with a 0.05 two-sided significance level. Furthermore, assessment of effects of hypo- and hyperinsulinemia on vascular reactivity via nitric oxide and insulin signaling proteins such as Akt and endothelial nitric oxide synthase combined with altered plasma levels of endothelin-1, asymmetric dimethylarginine and nitric oxide may elucidate mechanisms behind sevoflurane-induced MBF changes in diabetic patients-41.In conclusion, these pilot data suggest that sevoflurane anaesthesia decreases resting myocardial blood flow in type 2 diabetic patients compared to healthy controls. Further, we observed a trend towards a lower endothelium-independent vasodilation capacity in diabetic patients under sevoflurane anaesthesia. These data provide preliminary insight into myocardial responses in type 2 diabetic patients under general anaesthesia.BMI: Body mass index; CPT: Cold pressor test; CVR: Coronary vascular resistance; DBP: Diastolic blood pressure; HR: Heart rate; HRV: Heart rate variability; HDL: High-density lipoprotein cholesterol; LDL: Low-density lipoprotein cholesterol; MBF: Myocardial blood flow; MCE: Myocardial contrast echocardiography; MI: Mechanical index; ROI: Region of interest; RPP: Rate-pressure product; SBP: Systolic blood pressure.The authors declare that they have no competing interests.CSEB participated in performing the study, data analysis, statistics and writing of the manuscript. CEvdB supported the data analysis and writing of the manuscript. SAL participated in the design of the study and reviewed/edited the manuscript. CB participated in the design of the study, data analysis and reviewed/edited the manuscript. RAB participated in the design of the study, data collection and reviewed/edited the manuscript. All authors read and approved the final manuscript.


Objective: We aimed to present inferior vena cava (IVC) diameter as a guiding method for detection of relationship between IVC diameter measured noninvasively with the help of ultrasonography (USG) and central venous pressure (CVP) and evaluation of patient's intravascular volume status.Methods: Patients over the age of 18, to whom a central venous catheter was inserted to their subclavian vein or internal jugular vein were included in our study. IVC diameter measurements were recorded in millimeters following measurement by the same clinician with the help of USG both at the end-inspiratory and end-expiratory phase. CVP measurements were viewed on the monitor by means of piezoelectric transducer and recorded in mmHg. SPSS 18.0 package program was used for statistical analysis of data.Results: Forty five patients were included in the study. The patients had the diagnosis of malignancy (35.6%), sepsis (13.3%), pneumonia, asthma, chronic obstructive pulmonary disease (11.1%). 11 patients (24.4%) required mechanical ventilation while 34 (75.6%) patients had spontaneous respiration. In patients with spontaneous respiration, a significant relationship was found between IVC diameters measured by ultrasonography at the end of expiratory and inspiratory phases and measured CVP values at the same phases . There was no statistically significant association between IVC diameters measured by ultrasonography at the end of expiration and inspiration and measured CVP values at the same phases in mechanically ventilated patients.Conclusions: IVC diameter measured by bedside ultrasonography can be used for determination of the intravascular volume status of the patients with spontaneous respiration. Central venous pressure (CVP) measurement is used to determine need for or excess volume. An invasive method, such as central venous catheter placement, is required in order to measure the CVP. Complications such as arrhythmias, cardiac chamber injury, vascular-nerve injury, pneumothorax, hemothorax, local bleeding, hematoma, infection, thrombosis, occlusion, pulmonary embolism and post-phlebitic syndrome may occur with catheter placement.The aim of this study was to evaluate the relationship between inferior vena cava (IVC) diameter measured by ultrasonography (USG) non-invasively and central venous pressure and provide inferior vena cava diameter as a guiding method to evaluate patient's intravascular volume status.2O, and whom we could not visualize the inferior vena cava due to the large body habitus, excessive intra-abdominal bowel gas, or large amounts of intrathoracic air were excluded.This study was started after confirmation of Çukurova University Faculty of Medicine Ethics Committee. Patients over the age of 18, to whom a central venous catheter was inserted to their subclavian vein or internal jugular vein, who needed invasive hemodynamic monitoring, and admitted to Department of Emergency Medicine between January 2011 - September 2011, were included in the study. Written, informed consent for participation was obtained before ultrasonographic examination by him / herself if the patient was conscious or by relatives if the patient was unconscious. Patients who had not agreed to participate in the study, who had an intra-abdominal pressure over 12 cm HA data collection form was created in order to gather standard data. Patient’s age, sex, CVP and IVC diameter measurement values at inspiration and expiration, disease diagnosis, arterial blood pressure, heart rate, CVP catheter type, status of the patient's spontaneous or mechanical ventilation, airway pressure, tidal volume, respiratory rate, PEEP (Positive end-expiratory pressure), inspiratory pressure and abdominal pressure values were recorded in data collection form.2 - PaO2 values to over 100, respectively. PEEP was adjusted to be 5 cm H2O.Measurements were performed in patients with spontaneous breathing or mechanical ventilation. In mechanically ventilated patients, ventilator mode was set to volume controlled mode. Tidal volume is set to be 8 cc / kg, respiratory rate to 12 / min and FiOThe inferior vena cava diameter measurements were performed in the supine position with Philips HD3 ultrasound device and 3.5 MHz convex probe. Vena cava and aorta were determined with transverse examination by 3.5 MHz probe. Then probe was directed to longitudinal plane over vena cava. Heart was localized with cranial angulation in this plane. Then the point where hepatic veins empties into the inferior vena cava was found by reducing the angulation. The distance between outer limit of the vessel and inner limit of the vessel at the opposite wall was measured 2 to 3 cm from the right atrial border in a long-axis/subxiphoid view in order to standardize and optimize the measurements. Measurements were taken at the end of both inspiratory and expiratory phases and were recorded in millimeters. The method of IVC measurement is shown in During central venous pressure measurement, level of the right atrium was taken as reference (zero) level. The point at the level of the fourth costal cartilage and on the mid-axillary line was taken as a reference point. Central venous pressure was monitored by piezoelectric transducers on monitor. The clinician who performed measurements with USG was blinded for these CVP measurements. The results of CVP were detected in mmHg.2O were excluded from the study.The bladder was drained by a Foley urinary catheter while the patient in supine position before the measurement of intra-abdominal pressure. Then 50-100 ml of isotonic fluid was injected to the bladder in sterile conditions and the distal portion was clamped. Then, a 18-gauge needle was entered into output of urinary catheter. Needle was connected to a 3-way system and a water manometer. After filled with sterile fluid, the patient side of the manometer was opened. "0" point of the manometer was aligned to patient's pubic symphisis point and the point where the liquid column was read in cm. Thus, the bladder pressure (BP), so the intra-abdominal pressure was determined in cm H2O unit. Patients with an intra-abdominal pressure over 12 cm HSPSS 18.0 package program was used for statistical analysis of data. Categorical measurements were summarized as number and percentage and numerical measurements were as mean and standard deviation (where necessary median and minimum-maximum). Correlations between continuous measurements were analyzed by Spearman Correlation Coefficient. Statistical significance level for all tests was taken as p < 0.05.Forty five patients, to whom a central venous catheter was inserted at Department of Emergency Medicine, were included in the study. Twenty four patients were male (53.3%) and 21 were female (46.7%). Mean age was calculated as 58.3 ± 17.43 years. A subclavian catheter was inserted to 24 patients (53.3%) and a jugular catheter to 21 patients (46.7%). Eleven patients (24.4%) required mechanical ventilation while 34 (75.6%) patients had spontaneous respiration.The patients had been under follow up most commonly with the diagnosis of malignancy , sepsis , pneumonia, asthma, COPD  .The mean systolic arterial pressure value of the patients’ was 108.4 mmHg and the standard deviation was 32.173. Minimum systolic arterial pressure value was 45 mmHg and maximum systolic arterial pressure value was 203 mmHg. Mean diastolic arterial blood pressure value of all patients was 60.8 mm Hg, the standard deviation was 15.008. The minimum diastolic arterial pressure value was 30 mmHg; maximum systolic arterial pressure value was 90 mmHg. The average heart rate of patients was 98.87 / min, the standard deviation was 26.403. Minimum heart rate was 54 / min, maximum heart rate value was 172 / min.Patients, who were included in the study, were divided into two groups as patients with spontaneous breathing and mechanically ventilated patients, and IVC diameter values and CVP values at inspiration and expiration were compared separately .In group of patients with spontaneous breathing, a statistically significant relationship was found between average IVC diameter (22.323±8.655 mm) measured by ultrasonography at the end of expiration and average CVP (7.650±4.836 mmHg) at expiration (p = 0.002).In group of patients with spontaneous breathing, a statistically significant relationship was found between average IVC diameter (15.097±8.047 mm) measured by ultrasonography at the end of inspiration and average CVP (5.410±4.711 mmHg) at inspiration (p = 0.001).In mechanically ventilated patients group, a statistically significant relationship was not found between average IVC diameter (14.272±3.495 mm) measured by ultrasonography at the end of expiration and average CVP (8.730±5.676 mmHg) at expiration (p = 0.524).In mechanically ventilated patients group, a statistically significant relationship was not found between average IVC diameter (16.636±4.410 mm) measured by ultrasonography at the end of inspiration and average CVP (10.550±5.610 mmHg) at expiration ((p = 0.192).3 CVP is a value indicating right atrial pressure or right ventricular filling pressure. In its simplest terms, CVP is an indicator of intravascular fluid status and right heart function. In normal humans, changes in CVP are correlated with changes in left ventricular filling pressure. There are many factors affecting the value of CVP, such as cardiac performance, blood volume, vascular tone, increased intra-abdominal or intrathoracic pressure and vasopressor therapy.4 For this measurement, an invasive method such as a central venous catheter placement is required. Central venous catheter placement, an invasive procedure, has a 15% risk for early and late complications.5,6 In addition to these complications, there are some disadvantages such as prolonged hospitalization, increase in health care costs, reduced quality of life. For this reason, the use of a reliable non-invasive method for hemodynamic monitoring is needed.In patients admitted to the emergency department, CVP should be monitored in cases of shock, circulatory failure, massive infusion or transfusion requirement, situations with massive bleeding risk, situations where careful fluid resuscitation is a must such as in pediatric patients or patients with cardiac problems.7 Motions and size of IVC changes with respiration and total body fluid.8,9 Intrapleural pressure becomes negative during inspiration and causes an increase in venous return to the right side of the heart. A decrase happens in intraluminal pressure. Natori et al demonstrated that lumen of inferior vena cava begins narrowing at the beginning of the inspiratory, reaches the narrowest diameter at the end of inspiration, expands during expiration, the respiratory changes on inferior vena cava diameter reverse during Valsalva maneuver and positive pressure ventilation due to increase in intrathoracic pressure and inferior vena cava diameter measurement by ultrasonography is a valuable method for predicting central venous pressure.10The inferior vena cava is the biggest vein of venous system with low-pressure. The expansion of the vein reflects venous pressure changes to a certain extent. This change also reflects the excess of the intravascular volume. For this reason, the inferior vena cava diameter may be an important diagnostic tool in evaluation of hypovolemia and hypervolaemia.In our study, in patients with spontaneous respiration, a significant relationship between IVC diameters measured by ultrasonography at the end of expiratory and inspiratory phases and measured CVP values at the same phases. However, no such relationship was seen in mechanically ventilated patients. In patients with spontaneous breathing, IVC diameter measurement by non-invasive bedside ultrasonography method may provide an idea about CVP pressure, intravascular fluid deficit or excess of patients. In other studies, IVC diameter of patients with heart failure, dependent on hemodialysis, traumatic hemorrhagic shock, sepsis and dehydration were found to correlate with CVP pressure. IVC diameter measurement is a valuable method for clinician to guide the treatment and follow-up in cases of septic shock, decompensated heart failure, acute or chronic renal failure, insufficient fluid intake, other causes of hypotension .The difference of our study from the others in the literature is the study group. Our study group included the patients admitted to the emergency department with emergency conditions whereas the others were including different study groups such as hemodialysis patients, patients with hemorrhagic shock due to trauma, patients during cardiac surgery with ongoing conditions.8 In a study conducted by Tetsuka and colleagues, IVC diameter, circulating blood volume and body weight were found to be decreased by ultrafiltration in patients undergoing hemodialysis and especially a correlation was found between end-expiratory diameter of IVC and circulating blood volume.11 Kusaba et al, in their study including 28 chronic hemodialysis patients, observed gradual reduction in expiratory inferior vena cava diameter during dialysis compatible with the the amount of fluid taken and observed an increase after blood reinfusion following hemodialysis, and they have proved that the changes in IVC expiratory diameter are more significant than changes in IVC inspiratory diameter.12IVC was first shown by Weil as dilated in patients with right heart failure.13In a study conducted by Yanagawa et al; 30 patients with hemorrhagic shock due to trauma were compared in terms of IVC diameters measured by ultrasonography at admission and after fluid resuscitation, inadequate expansion in IVC diameter was found to be a possible indicator of inadequate circulating blood volume even if blood pressure was normal.8Lyon et al have found about 5 mm decrease in inspiratory and expiratory diameter of IVC following a 450 ml of blood donation by donors in a study on 31 voluntary people for detection of relationship between circulating blood volume decrease and a reduction in IVC diameter. They reported that assessment of IVC diameter by USG in patients with intravascular volume depletion due to trauma or other reasons may be beneficial.14 Marcelino et al also detected a correlation between CVP and caval index15 obtained by measurement of IVC diameter of 477 patients followed in surgical or medical intensive care units.16 Minutiello and colleagues compared CVP and caval index of 65 patients in their study and reported that caval index is in an inverse relationship with CVP value, and CVP is normal if caval index is ≥ 20% and is increased if caval index is < 20 %.17Lorsomradee et al performed a study on 70 patients in order to determine the correlation between inferior vena cava diameter and central venous pressure during cardiac surgery. They found a correlation between CVP and IVC diameter in patients with CVP equal to or smaller than 11 mmHg.18 In a study conducted by Lorsomradee and colleagues in 2007, after setting the PEEP value to 5 and 10 cm H2O during cardiac surgery, they found an increase in CVP and inferior vena cava diameter when PEEP value increased to 10 cm H2O from 5 cm H2O, but they could not find a correlation between CVP and the inferior vena cava diameter during PEEP ventilation.14 We think that the small number of mechanically ventilated patients in our study, no disconnection of patients from mechanical ventilator during IVC measurement, differences in modes and settings of mechanical ventilator seem to be effective in not finding a significant correlation between IVC diameter and CVP in mechanically ventilated patients. As possible changes in pleural pressure during mechanical ventilation will affect central venous pressure, patients with this condition must be separated from the ventilator during the measurement.19In our study, in 11 mechanically ventilated patients, there was no statistically significant relationship between IVC diameters measured by ultrasonography at the end of expiratory and inspiratory phases and measured CVP values at the same phases. Arthur et al found a statistically significant correlation between IVC and CVP in a 95 patient-included study in order to determine the relationship between central venous pressure and inferior vena cava diameter measured by transesophageal echocardiography in mechanically ventilated patients under general anesthesia.It was found that in patients with spontaneous respiration there is a significant relationship between IVC diameters measured by bedside ultrasonography at the end of expiratory and inspiratory phases and measured CVP values at the same phases and IVC diameter measurement can be used for the determination of intravascular volume status. It was found that this method can not be used in mechanically ventilated patients. This study will be useful regarding contribution to clinical experiences and appropriate treatment by emergency physicians with providing intravascular volume status of patients non-invasively. With more detailed and comprehensive studies, this method can be used as a routine.SC and AS conceived the idea and designed the study. AS and MOA were involved in the making of questionnaire and data collection. FI and AA analyzed the data. Interpretation of data was performed by all authors. MG and MS are secondary intellectual contributors. MOA and SS prepared the initial draft of the manuscript followed by critical revision of manuscript for important intellectual content by all the authors. Consensus of all authors was reached in finalization of draft for publication.


Inadequate blood pressure control and poor adherence to treatment remain among the major limitations in the management of hypertensive patients, particularly of those at high risk of cardiovascular events. Preliminary evidence suggests that home blood pressure telemonitoring (HBPT) might help increasing the chance of achieving blood pressure targets and improve patient’s therapeutic adherence. However, all these potential advantages of HBPT have not yet been fully investigated.n=84) or HBPT (n=168). The primary study endpoint will be the rate of subjects achieving normal daytime ambulatory blood pressure targets (<135/85 mmHg) 24 weeks and 48 weeks after randomization. In addition, the study will assess the psychological determinants of adherence and persistence to drug therapy, through specific psychological tests administered during the course of the study. Other secondary study endpoints will be related to the impact of HBPT on additional clinical and economic outcomes .The purpose of this open label, parallel group, randomized, controlled study is to assess whether, in patients with high cardiovascular risk , long-term (48 weeks) blood pressure control is more effective when based on HBPT and on the feedback to patients by their doctor between visits, or when based exclusively on blood pressure determination during quarterly office visits ). A total of 252 patients will be enrolled and randomized to usual care (The TELEBPMET Study will show whether HBPT is effective in improving blood pressure control and related medical and economic outcomes in hypertensive patients with metabolic syndrome. It will also provide a comprehensive understanding of the psychological determinants of medication adherence and blood pressure control of these patients.Clinical Trials.gov: NCT01541566 The prevalence of arterial hypertension in the European population is estimated to approximate 20%. HyperteAlthough numerous studies have shown that antihypertensive treatment may reduce cardiovascular risk and despite availability of several valuable antihypertensive drug options, today, no more than 30% of treated hypertensive patients maintain a satisfactory blood pressure control,7.This may be caused by many factors, among which poor or complete lack of adherence to treatment prescriptions have been reported to play a major role. Compliance to therapy seems to be related to many factors including the high number of pills to be taken daily, an excessive cost of the available medications, the lack of motivation and poor patient’s involvement in the management of this clinical condition, the long wait in the doctor’s office, the absence of symptoms, the inability of the patient to understand the real long-term consequences of high blood pressure, and finally the psychological and personality traits of the patients.Different solutions may be adopted in order to improve blood pressure control and patients’ adherence to therapy. An effective organization for a better management of this condition based on new technologies, through which the efficacy of therapy can be monitored, could help patients to get more involved in the daily care of their treatment, and to better cooperate with the physician. One of the methods used to obtain a better therapy adherence and therefore a more effective blood pressure control is now represented by self-measurement of blood pressure at home by automatic electronic devices. This meEvidence from randomized studies suggests that home blood pressure telemonitoring (HBPT), defined as home blood pressure monitoring coupled with telematic data transmission to the doctor and real-time feedback on patient’s status, may improve blood pressure control and compliance to treatment, and may help in optimizing the patient’s therapeutic regimen,21.Although HBPT may in particular be of great advantage for those patients requiring a closer follow-up, as in the case of high-risk hypertensive patients, at the moment it has not yet been clarified whether this approach may actually improve blood pressure control and adherence and persistence to antihypertensive drug treatment also in this category of hypertensive patients.vs. control).The study aims at investigating whether in high-risk patients with hypertension and metabolic syndrome, daytime ambulatory blood pressure control over 48 weeks is more effective when based on regular HBPT (intervention group), through monthly automated blood pressure teletransmission and feedback to the patient by the doctor, rather than when based only on periodic measurements made by doctors in their office during quarterly visits  control group). The main study endpoint will be the assessment and comparison of the rate of subjects achieving a daytime ambulatory blood pressure normalization (average daytime blood pressure <135/85 mmHg) in the two randomization groups  intervention group (HBPT), with automated teletransmission of home blood pressure values to the Investigator, every month, over the first 24 weeks, followed by manual transmission of self-measured blood pressure data to the HBPT center immediately before each office visit, with regular doctor’s visit every 3 months, in the second 24 weeks (see below for details); (2) control group (CM) managed only through regular office visit every 3 months. A flow chart of the study design is reported in Figure This is an Italian, multicenter trial involving 12 Hypertension Centers, of which seven are located in northern Italy, two in central Italy, and three in southern Italy. The study will be conducted according to Good Clinical Practice guidelines and the Declaration of Helsinki. The protocol will be approved by the Ethics Committees of the centers involved.The study will include hypertensive patients with metabolic syndrome, who are at an increased risk of cardiovascular events in the short term, and for whom adequate blood pressure control and treatment adherence are clinically relevant issues.In order to be eligible for inclusion in the study the patients have to comply with the following criteria: (1) male or female gender and age between 18 and 74 years; (2) untreated or treated, but uncontrolled, essential arterial hypertension (office systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mm mmHg plus average daytime ambulatory systolic blood pressure ≥135 mmHg and/or average daytime diastolic blood pressure ≥85 mm Hg); (3) presence of metabolic syndrome according to ATP-III criteria, namely Main exclusion criteria are: (1) secondary hypertension; (2) renal or liver impairment; (3) severe autoimmune diseases; (4) neoplasia; (5) atrial fibrillation, frequent ectopic beats or severe conduction disturbances (second and third degree atrio-ventricular block), which may make automatic blood pressure measurement difficult or unreliable; (6) an arm circumference >32 cm or <22 cm; (7) any other condition that might compromise the patient’s participation in the study, including illiteracy and diseases preventing the completion of questionnaires ; (8) patients not able to follow study procedures.Patients meeting inclusion criteria will be fully informed about the study design and purposes and asked to give a written informed consent, if willing to participate. After obtaining the written informed consent, eligible patients will be randomized to one of the two study arms.Randomization will be performed using a blocked randomization procedure (computerized random numbers), in order to obtain equal numbers in each study arm. Patients will be randomized to CM or HBPT (1:2). In order to prevent selection bias, the allocation sequence will be concealed from the Investigator enrolling and assessing patients in sequentially numbered, opaque, and sealed envelopes.At the time of the randomization, patients assigned to HBPT, will be equipped with an electronic blood pressure measuring device and a wireless transmitting interface. These devices will be kept at home until the end of the study.The patient will be adequately trained by the Investigator on measurement procedures. Patients will be asked to self-measure their blood pressure at home twice a day, using a validated, automatic, electronic, oscillometric, upper arm monitor . The devTwo measurements, at a 2-min interval, will be taken in the morning before going to work or before starting daily activities (between 08:00 and 10:00), and two measurements will be taken in the evening (between 18:00 and 22:00), for a minimum of 3 days a week. The measurements have to be taken in a quiet environment, with the patient in a relaxed, comfortable, sitting position for at least 5 min before self-measurement.http://www.morepress.net website,  where they will be analyzed and a report will be generated and sent once a month via email to the Investigator. A feedback on the status of patient’s blood pressure control will also be visualized on the interface display.After each measuring session and when not used for measuring blood pressure, the blood pressure monitor will be connected through a serial cable to a GPRS wireless interface (BluMed). During the first 24 weeks, the transmitter will send blood pressure data every day to theThe wireless interface also comes with a button which allows the patient to manually send the data to the HBPT center whenever it is deemed necessary , independently from the scheduled program. During the last 24 weeks of the follow-up no automatic data transmission will be done, but the patient will be requested to manually send to the HBPT center the self-measured blood pressure data, immediately before each scheduled office visit.A diagram of the telemonitoring web-based system is shown in Figure In the CM or control group, blood pressure will be measured only during the office visit by the same automatic device used by patients of the HBPT randomization group. After 5 min sitting, automated blood pressure measurements will be performed twice at a 2-min interval and the average of the measurements will be calculated and used as clinical reference.Besides baseline screening and randomization visits (Visit 1 and 2), all the patients will be re-assessed at 4 weeks Visit 3), 12 weeks (Visit 4), 24 weeks (Visit 5), 36 weeks (Visit 6), and 48 weeks (Visit 7) of follow-up. If the Investigator deems it appropriate extra visits can be planned. Figure , 12 weekThe study includes a first visit at the Hypertension Center (Visit 1) where automatic office blood pressure is measured, the patient’s history gathered, a physical examination performed. Laboratory tests useful for the determination of the organ damage and cardiovascular risk will be assessed as well. These tests include biochemistry and urinalysis , an echocardiogram with determination of left ventricular mass, a carotid ultrasonography for determination of intima-media thickness, a fundoscopy, and an electrocardiogram (ECG). Waist circumference will also be measured. A 24-h ambulatory blood pressure monitoring will be performed (see below for details).Within 1 week from Visit 1 those patients complying with the inclusion criteria  will be randomized to the CM group or to the HBPT group (Visit 2).During the same visit the patients will be administered the following psychological tests: Medical Outcome Survey Short-Form 36 (SF-36), Psychological General Well-Being Index (PGWBI), Beck Depression Inventory (BDI), Locus of Control (LoC), Self-Esteem Inventory (SEI), Illness Behaviour Questionnaire (IBQ) and Coping strategies (COPE), forming set 1, and Trait Anxiety Inventory (STAY), Type D Personality (TDP), Type A Personality (TAP), Temperament and Character Inventory (TCI), forming set 2-35. In uFour weeks later (Visit 3) the patients will be visited again by the Investigator and the medical therapy will be adjusted on the basis of office blood pressure  in the CM group or home blood pressure  in the HBPT group. Office blood pressure will still be measured by the Investigator with the same automatic electronic instrument used for self-measurement, in all patients, including those randomized to HBPT. Additional visits are scheduled 12, 24, 36, and 48 weeks after randomization . During each of these visits office blood pressure will be measured and antihypertensive medication will be changed according to office (CM group) or home blood pressure values (HBPT group). Drug treatment can also be changed in the patients of the HBPT between the scheduled visits, based on the home blood pressure report monthly received and reviewed by the Investigator. The same laboratory tests performed at screening visit and a 24-h ambulatory blood pressure recording will be repeated at Visits 5 and 7. During these two visits psychological tests will also be administered, with the exclusion of STAY, TDP, TAP, and TCI test, administered only at Visit 2.Occurrence of adverse events, adherence to therapy and concomitant therapies will be checked at all visits during the trial. Evaluation of adherence to drug treatment will be based on patient’s report on amount of prescribed drug intake and on counting the quantity of study medication taken by the patient, comparing this datum with the quantity expected to be returned. The Investigator will instruct each patient to bring back used and unused drug blisters at each visit. The compliance will be computed as the ratio between the number of pills taken and the number of pills which should have been taken, expressed as a percentage, and will then be graded as follows: excellent (100% of prescribed pills taken), good (80% to 99%), fair (40% to 79%), or poor (<40%).At Visit 1, and subsequently at Visit 5 and at final visit (Visit 7) an ambulatory blood pressure monitoring will be performed non-invasively over 24 h by an oscillometric validated device,37. CurrThe modality of self-blood pressure measurement at home has been detailed in the previous sections. In the HBPT group home blood pressure reports will be automatically transmitted to the Investigator every month for the first 12 weeks (from Visits 2 to 5). Based on these reports, the Investigator will be allowed to adjust drug treatment before the next visit or to schedule an extra study visit. Starting from Visit 5 until the end of the study (Visit 7), the patients randomized to HBPT will continue to self-measure blood pressure at home, but automatic transmission will be disabled and each patient will be asked to manually send blood pressure data the day immediately preceding the office visit at the Center. These home blood pressure measurements will be reviewed by the Investigator exclusively on Visits 6 and 7, and treatment adjusted accordingly.With the aim to investigate the psychological impact of HBPT clinical psychologists will assess psychological dimensions at Visits 2, 5, and 7 by using the following standardized questionnaires: (1) SF-36: a generic tool for assessing the quality of life, aiming at quantifying the impact of disease on general health and on the psychological profile, for the determination of the most characteristic aspects affecting quality of life in relation to a standard reference population(2) PGWBI: a tool for the assessment of psychological wellbeing(3) BDI: this test can be considered as a standard reference among the self-assessment scales. A key feature of the scale is the precise definition of the criteria for quantification, since every item corresponds to a given level of severity. The scale is the most specific self-assessment tool for depression, exploring a narrow range of symptoms by excluding those related to anxiety(4) LoC: this test measures the tendency to attribute the causes of behavior to internal or external conditions,28(5) SEI: this test measures the degree of self-esteem of the patient(6) IBQ: this test measures the disease perception(7) COPE: the test is designed to be a measuring instrument capable of assessing the more subtle individual differences in coping. It is able to balance the general trend of the subject with the current response to the stressful situation. Due to its characteristics, this test is suitable for studies aiming at clarifying more thoroughly the possible influence of personality aspects on adaptationIn order to investigate the personality traits underlying the adherence behavior, clinical psychologists will also assess the following psychological dimensions only at Visit 2 by using the following standardized questionnaires:(1) STAY: this test assesses the degree of trait anxiety severity(2) TDP: the test evaluates the presence of the personality traits defined as being distressed(3) TAP: the test evaluates the presence of type A personality traits(4) TCI: a questionnaire for the self-evaluation of different personality characteristics, normal and abnormal, which is based on an interpersonal theory of personalityAll psychological questionnaires used in the study are psychometrically validated and standardized on the Italian population.The primary study endpoints are (1) the percentage of patients achieving daytime blood pressure normalization (systolic blood pressure <135 mmhg and diastolic blood pressure <85 mmhg) 24 weeks after randomization (visit 5); and (2) the percentage of patients achieving daytime blood pressure normalization after 48 weeks (visit 7).The primary outcomes will be separately assessed for the HBPT and CM groups.A series of psychological and clinical variables will be used as secondary endpoints.Scoring of the different psychological questionnaires will be computed for the HBPT and CM groups and compared between groups. They will be used to quantify therapeutic adherence, and compared with evaluation of compliance based on the patient’s report.vs. baseline; (4) changes in office systolic and diastolic blood pressure after 24 and 48 weeks vs. baseline; (5) changes in average home systolic and diastolic blood pressure after 24 and 48 weeks vs. baseline in the HBPT group; (6) the number of antihypertensive drugs prescribed after 24 and 48 weeks vs. baseline; (7) the number of office or phone visits after 24 and 48 weeks vs. baseline; (8) direct costs of patient management, based on additional medical visits and laboratory tests performed between baseline and 24 and 48 weeks; (9) adherence to treatment, as reported by the patient ; (10) difference in target organ damage score between baseline and week 24 and 48 of the study; (11) difference in cardiovascular risk level between baseline and week 24 and 48 of the study according to Heart Score (ESH-ESC) and Framingham algorithm[The following clinical endpoints will also be evaluated: (1) the percentage of patients with office blood pressure normalization <140/90 mmHg) after 24 and 48 weeks; (2) percentage of patients with home blood pressure normalization (average <135/85 mmHg) after 24 and 48 weeks in the HBPT group; (3) changes in average 24-h systolic and diastolic blood pressure after 24 and 48 weeks /90 mmHg lgorithm; (12) diThe underlying study hypothesis is that the percentage of subjects achieving daytime blood pressure normalization will be 25% larger in the HBPT group. Using a two-tailed test with a 0.05 significance level and an 80% power, the estimated number of patients to be randomized is 252 (including a 25% drop-out rate), with 84 patients randomized to CM and 168 to HBPT.Analysis will be performed on patients valid for intention-to-treat, defined as all subjects with at least one visit during the randomized phase of the study and with valid ambulatory blood pressure recordings at baseline, after 24 and 48 weeks of follow-up even in the presence of protocol violations. A confirmatory analysis on the per-protocol (patients who have successfully completed the study without major protocol violations) is also foreseen.The demographic and clinical characteristics of the two study groups will be compared at baseline by analysis of variance (continuous variables) or by Mantel-Haenszel Chi-square test , in order to verify the between-group homogeneity at randomization. The same tests will be used to compare primary and secondary study endpoints between the CM and HBPT groups. If deemed necessary, in addition to the univariate approaches, multivariate analysis methods will be used.The type and frequency of drug-related adverse events will be reported for each randomization group. The absolute rate of adverse events will be compared between groups using the Chi-square test.P <0.05.The minimum level of statistical significance will be set at vs. usual care in improving blood pressure control in either low- or high-risk hypertensive patients[This article describes the background, objectives, and design of a randomized controlled trial that will test the superiority of HBPT as compared to CM in improving blood pressure control in high-risk hypertensive patients with metabolic syndrome. Our study will help adding further evidence on the effectiveness of treatment decision of hypertension based on home blood pressure monitoring or HBPT. Findings from previous studies are controversial to this regard. In the THOP (Treatment of Hypertension based on home or Office blood Pressure) trial, antihyppatients.Secondarily, the trial will investigate and compare between randomization groups personality traits predictive of adherence. This will be useful to identify possible psychological determinants of adherence to antihypertensive treatment, also relating them to blood pressure response to antihypertensive treatment in daily life conditions. Poor adherence to treatment remains one of the major limitations in the management of hypertension: it may cause poor blood pressure control and may contribute to increased morbidity, mortality, and costs,46.Previous studies have shown that persistence with antihypertensive therapy decreases with time: discontinuation rates vary from 22% to 50% of patients during the first year after treatment initiation-50. TherThe study will also evaluate the impact of HBPT on additional medical and economic outcomes, which might help in unmasking possible additional advantages of this technique in high-risk hypertensive patients, on a relatively long-term follow-up.Before drawing the conclusions we must acknowledge that the study protocol suffers from some potential methodological limitations. First, allocation of patients to one of the two study groups will be concealed from the Investigator by means of sequentially numbered, opaque, and sealed envelopes. We acknowledge that this approach may introduce a bias and that central computerized randomization would be preferred. However, web-based randomization was not possible due to limited availability of continuous Internet connection in some centers and telephone interactive voice response services could not be afforded because too expensive. Second, assessment of medication adherence will be based on both self-report of patients and on manual pill count by the Investigator. This methodology might be imprecise. However, adherence is not the primary study endpoint, and though the use of electronic pill-box monitoring was taken into account at the time of study planning and designing, we opted out of this choice because the device was too expensive and its management too complex for the study purposes.At the moment no studies have assessed the impact of HBPT and of the quantification of patient’s psychological characteristics on improvement of blood pressure control and adherence to antihypertensive treatment. The TELEBPMET Study will show whether this approach is effective in management of hypertensive patients with metabolic syndrome. It will also provide a comprehensive understanding of the psychological determinants of medication adherence and blood pressure control in high-risk patients with hypertension.The TELEBPMET study trial was conceived and designed in 2008. At the time this manuscript was submitted full approval by the Medical Ethics Committee has been obtained for all centers and recruitment was started. The patients’ follow-up is currently ongoing.ATP: Adult Treatment Panel; BDI: Beck Depression Inventory; CM: Conventional management; COPE: Coping Orientation to Problems Experienced; e-CRF: Electronic Case Report Form; ECG: Electrocardiogram; ESC: European Society of Cardiology; ESH: European Society of Hypertension; GPRS: General Packet Radio Service; HBPT: Home blood pressure telemonitoring; HDL: High density lipoproteins; IBQ: Illness Behavior Questionnaire; LoC: Locus of Control; PGWBI: Psychological General Well Being Index; SEI: Self-Esteem Inventory; SF: Short-Form; STAY: State-Trait Anxiety Inventory; TAP: Type A Personality; TCI: Temperament and Character Inventory; TDP: Type D personality.GP has received honoraria for lectures by Omron and Microlife companies, manufacturers of home blood pressure devices. SO is Scientific Consultant of Biotechmed Ltd., manufacturer of the Morepress telemedicine system used in this study. EG is Medical Director of Bracco Pharmaceuticals, the company sponsoring the project. All the other authors declare that they have no competing interests.GP, SO, and AC conceived the study. All authors participated in the trial design. SO and AC wrote the first draft of this manuscript. All authors commented on drafts of this paper, and read and approved the final manuscript.The Telebpmet Study GroupGianfranco Parati (Milano)Stefano Omboni (Varese), Tiziana Gazzola (Varese), Edward Callus (Milano)


Homoarginine is an amino acid derivative mainly synthesized in the kidney. It is suggested to increase nitric oxide availability, enhance endothelial function and to protect against cardiovascular diseases. We aimed to investigate the relation between homoarginine, kidney function and progression of chronic kidney disease (CKD).We measured plasma homoarginine concentrations in baseline samples of the Mild to Moderate Kidney Disease (MMKD) Study, a prospective cohort study of 227 patients with CKD in Europe. Homoarginine concentrations were available in 182 of the baseline samples and in 139 of the prospectively-followed patients. We correlated homoarginine concentrations to parameters of kidney function. The association between homoarginine and progression of CKD was assessed during a follow-up of up to seven years  using Cox regression analysis. Progression of CKD was defined as doubling of baseline serum creatinine and/or end-stage renal disease.Study participants were at baseline on average 47±13 years old and 65% were male. Mean±standard deviation of homoarginine concentrations were 2.5±1.1 µmol/L and concentrations were incrementally lower at lower levels of GFR with mean concentrations of 2.90±1.02 µmol/L (GFR>90 ml/min), 2.64±1.06 µmol/L (GFR 60–90 ml/min), 2.52±1.24 µmol/L (GFR 30–60 ml/min) and 2.05±0.78 µmol/L (GFR<30 ml/min), respectively (p = 0.002). The age- and sex-adjusted risk to reach the renal endpoint was significantly higher by 62% with each decrease by one standard deviation (1.1 µmol/L) of homoarginine . This association was independent of proteinuria , and was slightly attenuated when adjusting for GFR .Homoarginine concentrations are directly correlated with kidney function and are significantly associated with the progression of CKD. Low homoarginine concentrations might be an early indicator of kidney failure and a potential target for the prevention of disease progression which needs further investigations. Chronic kidney disease (CKD) represents a major public health problem with an increasing prevalence as well as an increase in the incidence rate of end-stage renal disease Homoarginine is a cationic amino acid, which is derived from lysine and mainly synthesized in the kidney by transaminidation of its precursor Therefore, we reasoned that a lack of homoarginine contributes to CKD progression: we hypothesized that a low blood concentration of homoarginine associates with a decline in kidney function and shorter time to end-stage renal disease. We therefore analyzed data of the Mild to Moderate Kidney Disease Study (MMKD Study), which is a prospective cohort study of 227 patients with primary nondiabetic CKD in Europe 2), organ transplantation, immunosuppressive treatment, allergy to ionic contrast media, treatment with fish oil or erythropoietin and pregnancy.The methodology of the MMKD Study has previously been reported in detail To avoid interobserver differences, all patients were recruited by a single investigator who visited all participating centers. Information on age, gender, smoking habits, comorbidities and antihypertensive treatment at baseline was recorded by patient interview and confirmed by checking patient records. A clinical examination completed the procedure. Body mass index (BMI) was calculated as weight (kg) divided by height (m) squared. Blood pressure was measured in sitting position. Hypertension was defined as BP>140/90 mmHg and/or the use of antihypertensive medication.The study was approved by the Institutional Ethic Committee of the University of Innsbruck, and all participants gave their informed consent before inclusion in the study.2; P<0.01]). However, both groups did not differ significantly with respect to age and gender. Patients who were lost to follow-up had moved away or were not referred by their physicians for follow-up visits in the renal units.Patients were followed prospectively until the primary study endpoint or the end of the follow-up period was reached. The primary endpoint was defined as doubling of baseline serum creatinine and/or terminal renal failure necessitating renal replacement therapy . A total of 177 (78%) patients from the baseline cohort of 227 patients could be followed prospectively over a period of up to 7 years. Patients received regular follow-up care in the outpatient ward and the endpoint was assessed by medical record abstraction. Patients who were lost to follow-up (n = 50) had at baseline a significantly better renal function than patients who were not lost to follow-up  and corresponding 95% confidence intervals per one standard deviation change of homoarginine for the progression to renal endpoints adjusted for age, sex, and other risk predictors of disease progression. The calculated Cox regression models did not violate the proportional hazards assumption. Moreover, using non-linear splines, models did not depart from linearity. A two-sided p-value<0.05 was considered statistically significant. Analyses were performed using SPSS for Windows version 18.0 and R 2.14.2.Continuous variables were compared between various groups using unpaired t tests or the nonparametric Wilcoxon rank sum test in case of non-normally distributed variables. Continuous variables across the stages of CKD were analyzed using one-way ANOVA or Kruskal-Wallis test where appropriate. Dichotomized variables were compared using Pearson χOf all 227 non-nephrotic patients included into the MMKD study, 182 patients with biological material available had a homoarginine measurement in the baseline samples. The mean homoarginine concentration was 2.57±1.09 µmol/L. Characteristics of patients with and without homoarginine values were not significantly different . The basOf the 177 patients in the MMKD study who could be followed prospectively until the end of the study or occurrence of the primary renal endpoint, a total of 139 patients had a homoarginine measurement available at baseline. Patients with and without homoarginine measurements and follow-up time were very similar in their clinical characteristics . The medWe performed Cox regression analyses considering the time of reaching the kidney endpoint . The ageIn additional analyses we investigated the role of nutritional status in the association of homoarginine with the progression of CKD. Neither BMI nor albumin was associated with the progression of kidney disease and the relationship of homoarginine with CKD progression was still significant after adjustments for albumin and BMI .This is the first study that describes plasma homoarginine concentrations in patients with primary non-diabetic chronic kidney disease not requiring dialysis. The main findings of this study are that 1) circulating homoarginine concentrations in CKD patients are significantly lower with lower GFR; 2) homoarginine concentrations were substantially lower in patients with kidney disease progression as compared to those without progression; 3) circulating homoarginine concentrations are inversely associated with the risk to reach a kidney endpoint, independently of age, sex and proteinuria. This association was slightly attenuated after additional adjustment for GFR (p = 0.06).Interestingly, up to now all parameters investigated in the MMKD Study showed a correlation of high concentrations with impaired kidney function as well as progression of CKD which points at a (direct or indirect) role of the kidney in their elimination In line with this, homoarginine is believed to derive mainly from endogeneous synthesis rather than from nutrition: Although it cannot be fully excluded that uptake from the diet contributes to normal endogenous homoarginine levels Our finding of an association of homoarginine with kidney function is furthermore in line with previous clinical studies. In the LURIC cohort comprising patients undergoing coronary angiography, homoarginine was significantly correlated to GFR with a correlation coefficient of 0.23 (p<0.001). The mean homoarginine concentration in this cohort was 2.6±1.1 µmol/L and patients had a mean GFR of 81±19 ml/min In a second and independent synthesis route, homoarginine can be formed within an alternative urea cycle. Through this cycle, homoarginine serves as a precursor of NO by increasing the intracellular concentration of L-arginine, which is the main substrate for NO synthase The previously shown experimental effects of homoarginine on blood pressure regulation and calcium-phosphate metabolism may represent further pathways by which homoarginine could potentially affect the course of kidney function. Previous studies found that administration of L-homoarginine increased urinary excretion of nitrate, the degradation product of NO, and reduced blood pressure in salt-sensitive hypertensive rats We consider it a strength of our study that GFR was not calculated by a formula but was measured by iohexol clearance which is considered an exact method to measure kidney function. In this context we refrained from investigating creatinine and cystatin C as surrogates of renal function, given that important novel findings pointed out the non-GFR related effects of these parameters Potential limitations of our study deserve also comments. Due to the observational design of our study, we cannot prove causality of the associations between homoarginine, kidney function and kidney disease progression. Furthermore, our study is limited by the sample size, and homoarginine measurements were not available in all patients of the MMKD Study. The lack of material in 38 patients out of 177 followed did not produce a particular selection bias: these 38 patients without homoarginine measurement were not different in major risk factors compared to those with measurements available see . FinallyWe have found homoarginine concentrations directly correlated with kidney function in patients with CKD. Furthermore, low homoarginine concentrations were significantly associated with the progression of kidney disease. Low homoarginine concentrations may be an early indicator of kidney failure and potentially useful as a marker of disease progression. Whether homoarginine metabolism is causally relevant for kidney disease progression deserves further studies including randomized controlled trials with homoarginine supplementation.Table S1Baseline clinical and laboratory data of 182 patients with homoarginine measurements available vs. 45 patients without measurements.(PDF)Click here for additional data file.Table S2Baseline clinical and laboratory data of the 177 patients who completed the follow-up. The patient group is stratified to 139 patients with homoarginine measurements available vs. 38 patients without measurements.(PDF)Click here for additional data file.


Stromal or mesenchymal neoplasms affecting the gastrointestinal (GI) tract have undergone a remarkable evolution in how they are perceived, classified, approached, diagnosed and managed over the last 30 years. Gastrointestinal stromal tumors (GIST) account for approximately 1% to 3% of all malignant GI tumors. The clinical features can vary depending on the anatomic location, size and aggressiveness of the tumor. Metastatic GIST represents a successful example of molecular targeted therapy. In this comprehensive review, we discuss the epidemiology, clinical features and diagnostic modalities for GIST. We also describe treatment options for early stage, locally advanced and metastatic GIST. Indications for neoadjuvant and adjuvant therapy along with duration of therapy are also explained. A brief discussion of latest biomarkers and updates from recent meetings is also provided. Stromal or mesenchymal neoplasms affecting the GI tract have undergone a remarkable evolution in how they are perceived, classified, approached, diagnosed and managed over the last 30 years. A major breakthrough occurred with the discovery of expression of the CD117 antigen by almost all gastrointestinal stromal tumors (GIST). The CD1GISTs account for approximately 1% to 3% of all malignant GI tumors . The estThe clinical features can vary depending on the anatomic location, size and aggressiveness of the tumor. Most symptomatic patients have tumors larger than 5 cm in maximal dimension. In a series of cases with leiomyomas and leiomyosarcoma (without separation of the GISTs), there were three major presentations , GI bleeGIST should always be among the differential diagnosis of an intra-abdominal non-epithelial malignancy. CT is essential for evaluating the primary tumor and for accurate staging. Magnetic resonance imaging (MRI) has a comparable diagnostic yield  and lackDifferentiation between GISTs and other tumors is typically based upon immunohistochemistry (IHC) and molecular analysis. Histologic findings seen on hematoxylin and eosin-stained sections do not reliably or specifically relate to the immunophenotype nor the molecular genetics of the lesions . GISTs cThe current consensus is to treat all GISTs, including those with a benign appearance by conventional histopathologic criteria, as having the potential to behave in a malignant fashion ,23. This18FDG-PET scanning could be very valuable to confirm the response to imatinib. After maximal response , definitive surgery could be performed [The natural history of early-stage GIST has been documented in single-institution studies. Two hundred patients with GIST were followed prospectively at the Memorial Sloan-Kettering Cancer Center . Eighty erformed .A large multicenter landmark phase 3 trial (ACOSOG study Z9001) appears to support the use of imatinib therapy in patients with larger, fully resected, primary localized GIST lesions at significant risk of relapse . Seven hThe FDA approved the use of imatinib as adjuvant therapy without any qualification or restriction following resection of primary GIST ≥3 cm in size, but the European Medicines Agency approved adjuvant imatinib only for the subset of GIST patients with primary disease that is judged to be “at significant risk of recurrence” following resection.Several criteria have been proposed, originally to classify the malignant potential of a GIST. Tumor size, mitotic rate, and site of tumor origin have gained the greatest acceptance as being predictive of outcome . Risk stAdjuvant imatinib for 1 year certainly has a major impact on disease control rates, but these differences appear to fade with increased rates of recurrence noted on discontinuation of the imatinib dosing. It is possible that a longer duration of adjuvant therapy might further improve clinical outcomes. A small study of adjuvant therapy for 2 years in Seoul, Korea has shown much higher rates of disease control than in the 1-year study, consistent with biological expectations . The resThe Intergroup EORTC 62024 trial with randomization between two years of imatinib and observation alone has been completed and is awaiting data maturation. OS is the primary end point. A single-arm phase II five-year adjuvant imatinib trial, PERSIST5, has also completed accrual; data probably will not be available for several years.Additionally, it is also important to assess whether certain GIST genotypic subsets benefit more—or fail to benefit at all—from adjuvant therapy with TKIs. The ACOSOG Z9001 randomized trial has confirmed certain differences between the behaviors of genetically different forms of GIST. The KIT exon 11 deletion confers a much higher risk of relapse compared with other mutational subtypes in the placebo arm, but these exon 11 mutants benefit from adjuvant imatinib to ablate this added risk . The PDGThere are no published randomized trials addressing the benefit of neoadjuvant imatinib in the management of GIST. Since 2003, several case reports and small retrospective series have been published. These include a mix of patients with borderline resectable and unresectable primary disease, as well as metastatic and locally recurrent disease that is potentially amenable to gross resection -57.The multicenter RTOG (Radiation Therapy Oncology Group) 0132/ACRIN (American College of Radiology Imaging Network) 6665 trial assessed neoadjuvant imatinib either in primary resectable GIST or as a planned preoperative cytoreduction agent for metastatic GIST . PatientData from retrospective series also support the benefit of initial imatinib therapy -56,60. TA small trial suggested response rates of up to 70% after very brief periods of neoadjuvant imatinib (three to seven days), as assessed by FDG-PET and dynamic CT . HoweverGuidelines from the NCCN recommend initial treatment with imatinib for patients with marginally resectable tumors and for those who have potentially resectable disease but with the risk of significant morbidity. A daily dose of 400 mg per day is the usual approach, although if a KIT exon 9 mutation is identified, dose escalation to 800 mg per day is reasonable. This is also recommended in ESMO guidelines .Various mechanisms are responsible for the resistance of GISTs to conventional cytotoxic chemotherapy. In one study evaluating the differences in outcome between GIST and leiomyosarcomas, significantly higher levels of expression of P-glycoprotein (38.4% vs. 13.4%) and MRP1 (35.4% vs. 13.3%) were demonstrated in the GIST cells .During the 1990’s, screening studies -67 demonCorrelative science studies have reported that the type of mutation in KIT and PDGFRA correlates with clinical response -77. HighRapid disease progression was seen within months after the imatinib is stopped ,81. At A18FDG [Imatinib can rapidly and dramatically decrease tumor avidity for 18FDG -86. With18FDG ,84,86. T18FDG ,87. Imat18FDG ,68,88. T18FDG ,90.Clonal evolution of resistant GIST may be detected after a durable objective response and disease control. Several mechanisms of resistance to imatinib in GIST may exist ,92. PharAs with imatinib, the clinical activity of sunitinib is significantly influenced by the specific mutation type. Resistance to sunitinib shares similar pathogenetic mechanisms to those identified in imatinib failure, with acquisition of secondary mutations after an extended initial response to the drug .Sorafenib and other TKIs  have been studied in refractory GIST or after resistance to imatinib and/or sunitinib ,100-105.Nilotinib was studied in a randomized phase 3 clinical trial (ENEST g3) . In thisThe survival was higher in GIST patients who had PDFGRA mutation as compared to KIT mutations. In patients with KIT mutations, point mutations and duplication in KIT axon 11 had better survival than GIST with other KIT mutations .p = 0.03) [In a single center study of GIST patients who underwent curative surgery and were not treated with imatinib, the 2 year RFS was lower in patients who had both 557 and 558 codon mutations than in those with either 557 or 558 mutated ( = 0.03) .Hypertension (HTN) is a side effect of drugs with VEGF signaling pathway inhibition. The relationship between sunitinib- associated HTN and treatment efficacy was analyzed. The results significantly favored the patients who developed HTN while on treatment with Sunitinib. These patients had significantly prolonged OS, PFS and TTP as compared to patients who did not develop HTN. Development of HTN during sunitinib therapy may therefore be used as a biomarker for anti-tumor efficacy .At ASCO GI 2012, a mitotic index of 5/50 HPF was reported to be equivalent to a standardized uptake value (SUV) of 4.3, and a Ki67 labeling index of 5 was equivalent to SUV of 6.3 on a PET-CT. Thus, an SUV of 5 can predict the malignant potential between the high and low/intermediate risk .D-dimer may be another potential marker in GIST . RadioloBillimoria et al. reported the evolution of multimodality management of GIST with adjuvant and neoadjuvant therapy. They found that between 2001 and 2007 use of adjuvant therapy with imatinib increased from 27% to 47%. Use of neo-adjuvant therapy increased from 0% to 15% in patients with tumors >6 cm . AlthougItaliano and co-workers reported the pattern of care, prognosis and survival in patients treated with first line Imatinib or second line Sunitinib in patients with GIST over 9 centers, including 176 patients. In the preliminary results they found that patients having secondary mutations and low serum albumin levels had the worst outcome .3 were independent predictors of overall survival. Patients with CD 34 positivity on tumors have a better PFS [BFR 14 is a prospective multicenter study from 2002 to 2009 which enrolled 434 patients. Blesius et al. reviewed 236 patients who were started on imatinib 400 mg daily and had been on it for 5 years. Patients who did not show any progression were retrospectively analyzed. They found that patients with small tumor volume at inclusion, good performance status, having exon 11 mutation in vicinity of codon 557–558 have higher sensitivity to imatinib and have a prolonged outcome as compared to other patients . Bertucctter PFS .With the molecular signature of CD117/KIT mutation, GIST has provided a great model for targeted therapy. Novel targeted agents are being explored -124.The authors have no conflicts of interests.SA, RG, BL contributed to data preparation. GL and DL were involved in concept design, data collection, and manuscript preparation. All authors reviewed and assisted in revising the manuscript. All authors read and approved the final manuscript.


The aim of this study was to determine the prevalence of gastrointestinal and behavioural symptoms occurring before (anticipatory/associative) and after methotrexate (MTX) administration, termed MTX intolerance, in rheumatoid (RA) and psoriatic arthritis (PsA).Methotrexate Intolerance Severity Score (MISS), previously validated in juvenile idiopathic arthritis patients, was used to determine MTX intolerance prevalence in 291 RA/PsA patients. The MISS consisted of four domains: abdominal pain, nausea, vomiting and behavioural symptoms, occurring upon, prior to (anticipatory) and when thinking of MTX (associative). MTX intolerance was defined as ≥6 on the MISS with ≥1 point on anticipatory and/or associative and/or behavioural items.A total of 123 patients (42.3%) experienced at least one gastrointestinal adverse effect. The prevalence of MTX intolerance was 11%. MTX intolerance prevalence was higher in patients on parenteral (20.6%) than on oral MTX (6.2%) (p < 0.001).Besides well-known gastrointestinal symptoms after MTX, RA and PsA patients experienced these symptoms also before MTX intake. RA and PsA patients on MTX should be closely monitored with the MISS for early detection of MTX intolerance, in order to intervene timely and avoid discontinuation of an effective treatment. Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are inflammatory disorders characterized by chronic arthritis ,2. In RAPreviously, we showed in juvenile idiopathic arthritis (JIA) that 50.5% of patients suffered not only from a myriad of gastrointestinal adverse effects after MTX intake, but also from adverse effects before MTX intake (anticipatory) and when thinking of MTX (associative) . The latThe aim of this study was to determine the type and prevalence of MTX-induced gastrointestinal adverse effects, with a standardized questionnaire, in a large cohort of RA and PsA patients.A cross-sectional descriptive study ISRCTN13524271) included RA and PsA patients attending the outpatient wards of four general hospitals between May 2011 and June 2012. All patients were treated with MTX for at least 3 months and received weekly folic acid (5 to 15 mg) [24271 incTo determine the prevalence of MTX-induced gastrointestinal adverse effects, patients completed the methotrexate intolerance severity score (MISS), previously developed and validated in JIA . The MISt-test, Mann–Whitney U-test). To evaluate associations of MTX intolerance with clinically relevant covariates - disease activity score (DAS)-28, physician global assessment (PGA), age, MTX dose, MTX route and non-steroidal anti-inflammatory drug (NSAID) use - multivariate logistic regression was performed. Statistical analyses were carried out with IBM SPSS Statistics, version 20.The prevalence was determined of: a) individual symptoms in all patients; b) MTX intolerance, defined as above; c) individual symptoms in MTX intolerant versus tolerant patients. MTX intolerance prevalence was compared between patients on oral and parenteral MTX (chi-square test). MTX intolerance severity, age, MTX dose, disease activity parameters and medication use were compared in tolerant versus intolerant patients, and in intolerant patients on oral versus parenteral MTX . Table One hundred and twenty-three 42.3%) RA and PsA patients experienced at least one gastrointestinal symptom during MTX treatment. The most prevalent gastrointestinal symptom after MTX administration was nausea, affecting 93 (32.0%) patients, whereas abdominal pain occurred in 11.3% and vomiting in 6.5% (Table .3% RA anMTX intolerance was found in 32 (11.0%) patients having a median score of 9 (IQR: 6.25 to 12.00). The prevalence and severity of MTX intolerance was similar in RA (n = 26 (10.4%), score 9 (6.8 to 12.3)) and PsA (n = 6 (14.3%), score 7 (6.0 to 13.0)). All intolerant patients (100%) experienced post-treatment nausea, whereas 46.9% had post-treatment abdominal pain and 31.3% had post-treatment vomiting (Table P < 0.001). MTX dose, DAS-28, PGA, erythrocyte sedimentation rate (ESR), co-medication use, history of peptic ulcers  and smoking  did not differ between the two groups. Gender distribution did not differ between MTX-intolerant and MTX-tolerant patients , but more female (75%) than male patients (25%) were intolerant, although this was not statistically significant.MTX-intolerant patients were younger than the MTX-tolerant  (Table P = 0.02), whereas other symptoms were comparable between the two groups. The median MTX intolerance score was higher in intolerant patients on parenteral than on oral MTX, although not significantly  versus 7.5, IQR 6.0 to 9.0), P = 0.08). Patients on parenteral MTX received the same MTX dose  as patients on oral MTX .MTX intolerance prevalence was significantly higher in patients on parenteral  than on oral MTX . If age was stratified into two groups, namely ≥65 and <65 years, older patients were again less likely to have MTX intolerance  whereas patients with higher PGA  and those receiving parenteral MTX  were more likely to have MTX intolerance.In the multivariate analysis, older patients were less likely to have MTX intolerance (odds ratio (OR) 0.93, 95%m, CI 0.89, 0.97; We showed that besides the well-known MTX-induced gastrointestinal symptoms upon MTX administration, RA and PsA patients also had anticipatory and associative gastrointestinal and behavioural symptoms before MTX administration, collectively termed MTX intolerance. MTX intolerance prevalence in RA and PsA patients was 11%.Studies in RA have found similar occurrence rates compared to our study ,11; nausP = 0.003). Substantially lower MTX intolerance prevalence in RA/PsA was due to: a) lower percentage of adults with score ≥6, and b) lower percentage of adults (24.4% versus 67% in JIA) with at least one anticipatory, associative and/or behavioural symptoms. As anticipatory and associative symptoms arise as classic conditioning responses to physical symptoms upon MTX use, the lower percentage of RA/PsA patients with pre-treatment symptoms suggests a weaker, classic, conditioning response in adults than in children taking MTX. This is supported by the fact that, whereas 82% of 204 JIA patients with symptoms after MTX also had symptoms before MTX intake, only 51% of 106 RA/PsA patients with symptoms after MTX had symptoms before MTX intake.In contrast to JIA in which the prevalence of MTX intolerance reached 50.5%, the prevalence in RA/PsA was considerably lower at 11%. MTX intolerance severity was lower in adults (score 9) than in children (score 12)  than on oral MTX (6.2%), which we also demonstrated for JIA ,14. ThisBesides the observed association between parenteral MTX and MTX intolerance, age was also associated with MTX intolerance, namely older patients (>65 years) were less likely to have MTX intolerance than younger patients (≤65 years). In previous studies, neither younger nor older age (>65 years) was associated with occurrence of MTX-related gastrointestinal and other side effects ,16. ValiAnticipatory and associative gastrointestinal symptoms could have a negative impact on patients’ quality of life  and impeAlthough the MISS was validated and employed to measure MTX intolerance prevalence in JIA, it provided a structured platform to assess the type of MTX-induced gastrointestinal symptoms in RA/PsA. Nevertheless, the MISS should be validated in adults with rheumatic diseases. Furthermore, this study does not reveal variables associated with MTX intolerance development, nor does it demonstrate the frequency of MTX discontinuation or of switching to other medication due to MTX intolerance. Prospective trials are required to address these issues.This is the first study to demonstrate using a standardized questionnaire, that MTX intolerance occurs in 11%, more frequently in patients on parenteral than on oral MTX, and possibly persists after a switch from oral to parenteral MTX. Since persistent gastrointestinal symptoms are the major reason to discontinue MTX, intolerant patients could be more prone to stop MTX or switch to (less effective) DMARDs or expensive biological agents . Upon vaUsing a standardized MISS questionnaire, we showed that besides the well-known MTX-induced gastrointestinal symptoms upon MTX administration, RA and PsA patients also experienced anticipatory and associative gastrointestinal and behavioural symptoms before MTX administration, which develop as a classical conditioning response to physical symptoms after MTX. The prevalence of MTX intolerance was 11%. MTX intolerance occurred more often in patients on parenteral (20.6%) than in those on oral MTX (6.2%) and persisted after a switch from oral to parenteral MTX. As persisting MTX intolerance could have a negative impact on patients’ quality of life and hamper the use of MTX, RA and PsA patients on MTX should be monitored with the MISS for early detection of MTX intolerance. This would create a window of opportunity to intervene timely and avoid incompliance and discontinuation of an otherwise efficacious treatment.DAS: Disease activity score; DMARD: Disease-modifying anti-rheumatic drug; ESR: Erythrocyte sedimentation rate; JIA: Juvenile idiopathic arthritis; MISS: Methotrexate intolerance severity score; MTX: Methotrexate; NSAID: Non-steroidal anti-inflammatory drug; OR: Odds ratio; PGA: Physician global assessment; PsA: Psoriatic arthritis; RA: Rheumatoid arthritis.The authors declare that they have no competing interests.MBĆ: substantial contribution to conception and design, acquisition of data, analysis and interpretation of data; involved in drafting the manuscript and revising it critically for important intellectual content; final approval of the version to be published. OvdB: substantial contribution to acquisition of data, analysis and interpretation of data; involved in drafting the manuscript; final approval of the version to be published. MCr: substantial contribution to acquisition of data; involved in revising the manuscript critically for important intellectual content; final approval of the version to be published. MCu: substantial contribution to acquisition of data; involved in revising the manuscript critically for important intellectual content; final approval of the version to be published. AH: substantial contribution to acquisition of data; involved in revising the manuscript critically for important intellectual content; final approval of the version to be published. JMvW: substantial contribution to acquisition of data; involved in revising the manuscript critically for important intellectual content; final approval of the version to be published. NW: substantial contribution to conception and design and interpretation of data; involved in revising the manuscript critically for important intellectual content; final approval of the version to be published. All authors read and approved the final manuscript.


Ganglion, a benign cyst, most common soft tissue tumor of the hand, usually occurs in the hand, wrist, and foot. It is difficult to treat as reoccurrence is common after surgery and also following other treatment procedures. In this study, sclerotherapy technique in 20 patients treated using a solution of tetracycline after aspiration is described. Most of the patients in this study were between the ages of 20 and 35 years. 16 patients had ganglion on the dorsum of the wrist, 2 patients had bilateral ganglion, and 2 patients had ganglion on the dorsum of the foot. Under aseptic conditions, the ganglions were aspirated using size 21 G needles, and then 1 mL equivalent to 100 mg/mL solution of tetracycline was injected. In the postoperative followup ranging between 18 months to 5 years, 2 reoccurrences were noticed that required the same technique. This procedure is simple, safe, effective, and cheap when compared to surgery and other nonsurgical procedure of treating ganglion. Ganglion accounts for two-thirds of all hand tumours . The comGanglion also occurs on the dorsum of the foot. Surgical treatment is required when they cause symptoms. The common indications for surgery are pain or the size of the ganglion for cosmetic reasons. Recurrence after surgical excision is extremely common . An alternative to surgical excision is aspiration with or without injection of local steroids and various other techniques , 4.This is a preliminary report of the result of aspiration followed by instillation of tetracycline as a sclerosant. This procedure is simple, cheap, and has several advantages which outweigh the benefit of surgery. The advantages are the following.No need for anesthesia, local or general.No scar and hence better cosmetic result.It is an office procedure without any complication such as hand edema and peripheral nerve injuring, and above all it is cost effective when compared to cost of surgical therapy.This prospective study commenced in September 2002 and is still ongoing. This study had approval of the hospital ethical committee in accordance with the Helsinki Declaration of 2010. The patients in this study have been followed up for a minimum of 18 months and some up to 5 yrs with no sign of recurrence. The major complaint was cosmetic as well as pain.Each patient has his or her ganglion aspirated with 5 mL syringe and 21 G needle. The gelatinous mucous material was aspirated. The content was completely empty, and this was evident by the slight bleeding at the end of procedure. While maintaining the needle in the cavity of the ganglion, 1 mL of tetracycline equivalent to 100 mg/mL  was injected. The needle is withdrawn, and a crepe bandage was applied. The same amount of sclerosant 1 mL was used regardless of the size of the ganglion. Again it was one brand of tetracycline from the same manufacturer  that was used, hence there may be little or no variation in the contents. I am not aware of the previous use of tetracycline sclerotherapy for ganlion and it was its sclerosant properties that were exploited for probable benefit in this study.The entire patients were given nonsteroidal anti-inflammatory drugs as analgesic because of the initial burring effect. Patients were seen at the SOPD 72 hours after therapy when the bandage was removed. There were then followup for a minimum of 18 months to see if there is any recurrence.A total of 20 patients have so far been treated in the last 5 years. There were 14 females (70%) and 6 males (30%), and age range was between 20–70 years. Most patients were between ages of 20 to 35 years, and most of the ganglion occured in the dorsum of the right wrist joint 16/20 (80%). 2 patient 2/20 (10%) had bilateral ganglion. 2 patients (10%) had ganglion on the dorsum of the foot (ankle joint) anteriorly. 18 (90%) patients had sclerotherapy once with good result. 2 patients had a repeat therapy before the ganglion was successfully treated. Both patients were those who had recurrence after surgical excision.Despite the benign nature of a ganglion, it can be problematic . GangliaThey are usually single and can affect any joint of the hand, wrist, and foot, but the dorsum of the wrist is the most common location as seen in this study. Ganglion is prevalent during the second and third decades of life, and this study has similar findings: 19 out of 20 patients were in the late twenties and early thirties only one patient was 70 yrs. Women are more affected than men, this is reflected in this study, 14 out of 20 70%) were females. It is said to occur with equal frequency in the dominant and assertive hand , 7. Howe0% were fThe indications for treatment are cosmetic, pains, and weakness of the hand. Nonsurgical treatment such as digital pressure, steroid, lidocaine injections, simple aspiration, heat, radiation, or sclerotherapy have been reported to be either not effective, with recurrence rates as high as 60%, or have limited success –11.In this study, sclerotherapy with tetracycline has success rate that surpassed the general rates quoted for this form of treatment. So far 90% of the patients had sclerotherapy once with a good outcome. 10% had reoccurrence which occur within 3 months but was successfully treated at the second attempt.The failure in these two patents is either as a result of previous surgery which altered the cyst wall or as result of the technical fault as this technique has been refined.Several agents have been used in sclerotherapy. These include phenol, 4 hyaluronidase, 2 and OK 432  with modMoreover, it is easily available, and the quality can be easily standardized and reconstituted even in the rural areas. This treatment is easily available and can be carried out by any doctor in contrast to surgery where good outcome depends on surgical experience, technique, and expertise. It is recommended that, when sclerotherapy is used, a maximum of 3 attempts should be done, before failure is assumed , 13. In This study is preliminary findings; it will be expanded with more cases and a longer followup to establish the effectiveness of tetracycline sclerotherapy.In conclusion, tetracycline sclerotherapy is judged to be very effective, easily available, requires little or minimal expertise, and is cheap and cost effective when compared to surgery. The success rate also appears to surpass surgery.