Permeability estimates in histopathology-proved treatment-induced necrosis using perfusion CT: can these add to other perfusion parameters in differentiating from recurrent/progressive tumors?

BACKGROUND AND PURPOSE: Differentiating treatment effects from RPT is a common yet challenging task in a busy neuro-oncologic practice. PS probably represents a different aspect of angiogenesis and vasculature and can provide additional physiologic information about recurrent/progressive enhancing lesions. The purpose of the study was to use PS measured by using PCT to differentiate TIN from RPT in patients with previously irradiated brain tumor who presented with a recurrent/progressive enhancing lesion. MATERIALS AND METHODS: Seventy-two patients underwent PCT for assessment of a recurrent/progressive enhancing lesion from January 2006 to November 2009. Thirty-eight patients who underwent surgery and histopathologic diagnosis were included in this analysis. Perfusion parameters such as PS, CBV, CBF, and MTT were obtained from the enhancing lesion as well as from the NAWM. RESULTS: Of 38 patients, 11 were diagnosed with pure TIN and 27 had RPT. Patients with TIN showed significantly lower mean PS values than those with RPT (1.8 ± 0.8 versus 3.6 ± 1.6 mL/100 g/min; P value=.001). The TIN group also showed lower rCBV (1.2 ± 0.3 versus 2.1 ± 0.7; P value<.001), lower rCBF (1.2 ± 0.5 versus 2.6 ± 1.7; P value=.004), and higher rMTT (1.4 ± 0.4 versus 1.0 ± 0.4; P value=.018) compared with the RPT group. CONCLUSIONS: PCT and particularly PS can be used in patients with previously treated brain tumors to differentiate TIN from RPT. PS estimates can help increase the accuracy of PCT in differentiating these 2 entities.

Regulation of butyrate uptake in Caco-2 cells by phorbol 12-myristate 13-acetate.

Butyrate and the other short-chain fatty acids (SCFAs) are the most abundant anions in the colonic lumen. Also, butyrate is the preferred energy source for colonocytes and has been shown to regulate colonic electrolyte and fluid absorption. Previous studies from our group have demonstrated that the HCO(3)(-)/SCFA(-) anion exchange process is one of the major mechanisms of butyrate transport across the purified human colonic apical membrane vesicles and the apical membrane of human colonic adenocarcinoma cell line Caco-2 and have suggested that it is mainly mediated via monocarboxylate transporter-1 (MCT-1) isoform. However, little is known regarding the regulation of SCFA transport by various hormones and signal transduction pathways. Therefore, the present studies were undertaken to examine whether hydrocortisone and phorbol 12-myristate 13-acetate (PMA) are involved in a possible regulation of the butyrate/anion exchange process in Caco-2 cells. The butyrate/anion exchange process was assessed by measuring a pH-driven [(14)C]butyrate uptake in Caco-2 cells. Our results demonstrated that 24-h incubation with PMA (1 microM) significantly increased [(14)C]butyrate uptake compared with incubation with 4alphaPMA (inactive form). In contrast, incubation with hydrocortisone had no significant effect on butyrate uptake in Caco-2 cells compared with vehicle (ethanol) alone. Induction of butyrate uptake by PMA appeared to be via an increase in the maximum velocity (V(max)) of the transport process with no significant changes in the K(m) of the transporter for butyrate. Parallel to the increase in the V(max) of [(14)C]butyrate uptake, the MCT-1 protein level was also increased in response to PMA incubation. Our studies demonstrated that the butyrate/anion exchange was increased in response to PMA treatment along with the induction in the level of MCT-1 expression in Caco-2 cells.

Database Conference January 27-30, 2000, Washington D.C.--Do existing databases answer clinical questions about geriatric cardiovascular disease and stroke?

EXECUTIVE SUMMARY: Most randomized, controlled trials evaluating the effectiveness of pharmaceutical, surgical, and device interventions for the prevention and treatment of cardiovascular disease have excluded patients over 75 years of age. Consequently, the use of these therapies in the older population is based on extrapolation of safety and effectiveness data obtained from younger patients. However, there are many registries and observational databases that contain large amounts of data on patients 75 years of age and older, as well as on younger patients. Although conclusions from such data are limited, it is possible to define the characteristics of patients who did well and those who did poorly. The goal of this conference was to convene the principal investigators of these databases, and others in the field of geriatric cardiology, to address questions relating to the safety and effectiveness of treatment interventions for several cardiovascular conditions in the elderly. Seven committees discussed the following topics: (I) Risk Factor Modification in the Elderly; (II) Chronic Heart Failure; (III) Chronic Coronary Artery Disease: Role of Revascularization; (IV) Acute Myocardial Infarction; (V) Valve Surgery in the Elderly; (VI) Electrophysiology, Pacemaker, and Automatic Internal Cardioverter Defibrillators Databases; (VII) Carotid Endarterectomy in the Elderly. The chairs of these committees were asked to invite principal investigators of key databases in each of these areas to discuss and prepare a written statement concerning the available safety and efficacy data regarding interventions for these conditions and to identify and prioritize areas for future study. The ultimate goal is to stimulate further collaborative outcomes research in the elderly so as to place the treatment of cardiovascular disease on a more scientific basis.

Sulfate and chloride transport in Caco-2 cells: differential regulation by thyroxine and the possible role of DRA gene.

The current studies were undertaken to establish an in vitro cellular model to study the transport of SO and Cl(-) and hormonal regulation and to define the possible function of the downregulated in adenoma (DRA) gene. Utilizing a postconfluent Caco-2 cell line, we studied the OH(-) gradient-driven (35)SO and (36)Cl(-) uptake. Our findings consistent with the presence of an apical carrier-mediated (35)SO/OH(-) exchange process in Caco-2 cells include: 1) demonstration of saturation kinetics [Michaelis-Menten constant (K(m)) of 0.2 +/- 0.08 mM for SO and maximum velocity of 1.1 +/- 0.2 pmol x mg protein(-1) x 2 min(-1)]; 2) sensitivity to inhibition by DIDS (K(i) = 0.9 +/- 0.3 microM); and 3) competitive inhibition by oxalate and Cl(-) but not by nitrate and short chain fatty acids, with a higher K(i) (5.95 +/- 1 mM) for Cl(-) compared with oxalate (K(i) = 0.2 +/- 0.03 mM). Our results also suggested that the SO/OH(-) and Cl(-)/OH(-) exchange processes in Caco-2 cells are distinct based on the following: 1) the SO/OH(-) exchange was highly sensitive to inhibition by DIDS compared with Cl(-)/OH(-) exchange activity (K(i) for DIDS of 0.3 +/- 0.1 mM); 2) Cl(-) competitively inhibited the SO/OH(-) exchange activity with a high K(i) compared with the K(m) for SO, indicating a lower affinity for Cl(-); 3) DIDS competitively inhibited the Cl(-)/OH(-) exchange process, whereas it inhibited the SO/OH(-) exchange activity in a mixed-type manner; and 4) utilizing the RNase protection assay, our results showed that 24-h incubation with 100 nM of thyroxine significantly decreased the relative abundance of DRA mRNA along with the SO/OH(-) exchange activity but without any change in Cl(-)/OH(-) exchange process. In summary, these studies demonstrated the feasibility of utilizing Caco-2 cell line as a model to study the apical SO/OH(-) and Cl(-)/OH(-) exchange processes in the human intestine and indicated that the two transporters are distinct and that DRA may be predominantly a SO transporter with a capacity to transport Cl(-) as well.

Recurrent and de novo non-alcoholic steatohepatitis following orthotopic liver transplantation.

BACKGROUND: Non-alcoholic steatohepatitis was coined in 1980 to describe pathological and clinical features of non-alcoholic disease associated with pathological features, commonly seen in alcoholic-liver disease itself. It is now a well-recognised cause of end-stage liver disease and a rare cause of orthotopic liver transplantation. A small number of cases with recurrent non-alcoholic steatohepatitis following liver transplantation have been reported, however de novo non-alcoholic steatohepatitis in the liver allograft is not well recognised. AIMS/RESULTS: We report four cases of non-alcoholic steatohepatitis following orthotopic liver transplantation describing the factors related with the pathology. The recurrence of fatty infiltration occurred within 21 months and transition from mild steatosis to non-alcoholic steatohepatitis and early fibrosis was observed within 60 months post transplant in all four patients. All four cases had association with one or multiples risk factors (obesity, type 2 diabetes and/or hyperlipidemia). CONCLUSIONS: Management of this risk factors may play a therapeutic role in the prevention of recurrent and de novo non-alcoholic steatohepatitis following orthotopic liver transplantation.

Increased incidence of chronic rejection in adult patients transplanted for autoimmune hepatitis: assessment of risk factors.

BACKGROUND/AIM: It remains uncertain whether autoimmune hepatitis (AIH), as an original indication for orthotopic liver transplantation (OLTX), predisposes to the development of chronic rejection (CR) after surgery and published reports on heterogeneous groups of patients provided conflicting data. In this work we analyzed the incidence and risk factors for CR in a large cohort of adult patients transplanted for AIH in our unit. RESULTS: A total of 1190 adult patients received OLTX in our center between 1982 and 1998. A total of 77 patients (6.5%) were transplanted for AIH and 12 (15.6%) patients from this group developed clinical and histological features of CR within a median time of 3.5 months after OLTX. Patients with AIH who developed CR were younger than other AIH patients at OLTX (32 vs. 44.2 ys; P=0.015) and more often had histological features of moderate or severe acute rejection (83 vs. 34%; P=0.002) on early post-OLTX biopsies. The incidence of CR in AIH patients was significantly higher than in subjects transplanted for other indications such as primary biliary cirrhosis (8.2%; P<0.05), primary sclerosing cholangitis (5.2%; P<0.05) or alcoholic cirrhosis (2.0%; P<0.001). Also, we observed a tendency to decreased incidence of CR with time in all transplanted subjects. CONCLUSIONS: Apart from younger age at OLTX and higher incidence of severe acute rejection, patients with AIH who developed CR did not differ from other subjects transplanted for this indication. Unlike other studies, not stratified by diagnosis, recipient CMV negative status, young donor age, and HLA DR matching were not identified as risk factors for CR in AIH.

Evaluation of endoscopy-based diagnostic methods for the detection of Helicobacter pylori.

BACKGROUND: Helicobacter pylori is an etiological factor in duodenal ulcer. Few studies have objectively assessed the accuracy of diagnostic methods for the detection of H. pylori. METHODS: The sensitivity and specificity of histology, touch smear, rapid urease test (RUT) and brush cytology of endoscopic antral biopsy from patients with duodenal ulcer were compared. Forty-nine patients were evaluated before, and 34 after, eradication therapy. Each time, sampling was done for all 4 tests. The infection status for each sample was established by a positive concordance of results of three of four tests. RESULTS: The highest degree of agreement was between RUT and cytology (kappa = 0.69). Brush cytology (100%) followed by RUT (94.5%) were the most sensitive tests. Histology had the highest specificity (89.3%). A combination of RUT or brush cytology with histology had the maximum chance of detecting H. pylori. As single tests, brush cytology and touch smear had high diagnostic accuracies with a Youdin J value of 1.79 and 1.78, respectively. CONCLUSION: The best method for diagnosis of H. pylori is a combination of the rapid urease test or brush cytology with histology. Brush cytology or touch smear are diagnostic tests of choice if a single test is desired.

Clinical and socioeconomic profile of patients with malignant ventricular arrhythmias in 1993 to 1995. AVID investigators. Antiarrhythmics Versus Implantable Defibrillator.

This report summarizes the clinical and socioeconomic characteristics of the first 542 patients entered into the Antiarrhythmics Versus Implantable Defibrillator (AVID) trial. AVID is a multicenter trial comparing a strategy of initial implantable cardioverter-defibrillator placement to initial antiarrhythmic drug therapy in preventing death in patients resuscitated from cardiac arrest who were not taking amiodarone and who did not have an implantable cardioverter-defibrillator in place at the time of the index event. These patients were randomly assigned to immediate defibrillator placement or to "best" medical therapy. Clinical and socioeconomic histories were collected by interview using standard terms developed for the study. Patients without (group 1) and with (group 2) a history of prior cardiac arrest were compared. The mean age of the 542 patients was 65 +/- 10 years, most were men, white, had coronary disease, and were highly functional despite the fact that only a minority were employed. Almost all had some form of health insurance. At the time of the index event, few were taking any therapy to prevent cardiac arrest, even in the group of patients with a history of previous cardiac arrest. Thus, the clinical and socioeconomic profile of patients resuscitated from sudden cardiac death entered into the AVID study is generally as expected. There is a striking absence of any attempt at chronic therapy to prevent cardiac arrest in most patients with a prior ventricular tachycardia or ventricular fibrillation.

Nonpharmacological therapy for malignant ventricular arrhythmias: implantable defibrillator trials.

Implantable cardioverter-defibrillators (ICDs) are an important nonpharmacological option in the treatment of malignant ventricular arrhythmias. Technological advances in current devices permit nonthoracotomy implantation with transvenous lead systems using biphasic shocks. Decreasing device size has resulted in pectoral implantation. Battery longevity is still short in comparison with that of pacemakers. Lead failure rates as well as pacing thresholds are significantly higher than those for cardiac pacing lead systems. Other complications of ICD systems include infection, perforation, and thrombosis. The long-term performance of nonthoracotomy lead systems for ICD devices has now been extensively studied. Sudden death recurrence rates for these systems are less than 2% in 3 years and less than 5% at 5 years. Clinical trials with both monophasic and biphasic systems show a high degree of prevention of sudden death. Comparison of ICD outcome with that of drug therapy in three large retrospective studies and two small prospective randomized trials favors improved survival and sudden death prevention with device therapy. However, these studies need corroboration from large prospective trials. Two large prospective trials, CIDS and the AVID study, are now in progress to address this issue.

Implanted cardioverter-defibrillators are preferable to drugs as primary therapy in sustained ventricular tachyarrhythmias.

The choice of initial therapy for patients with malignant ventricular tachyarrhythmias is examined based on clinical efficacy, patient safety, and cost. Antiarrhythmic drug therapy can be administered using a guided or empiric approach. Guided type-1 antiarrhythmic drug therapy has been associated with high arrhythmia recurrence rates (> 40% at 1 year) and moderate sudden death rates (10% at 1 year). Sotalol is associated with lower arrhythmia recurrence rates (20% at 1 year) that increase to 50% at 4 years. Beta-blocking agents have a limited role as stand-alone therapy in this condition. Empiric amiodarone therapy has sudden death-free survival rates of 82% at 2 years but has significantly poorer results in patients with ejection fractions < or = 40%. In contrast, implantable cardioverter-defibrillator (ICD) therapy has reported sudden death recurrence rates of 1% to 2% per year, with a cumulative index of 10% at 5 years. Total survival rate of ICD recipients ranges from 85% to 92% at 2 years. In patients with good left ventricular function, it approaches 90% at 5 years, whereas it is between 50% to 60% in patients with severe left ventricular dysfunction. Data from device memory indicate an absolute reduction in mortality rates with ICD intervention. Comparison of drug and device therapy has been performed in retrospective and prospective studies. Improved survival with device therapy is noted, particularly in patients with ejection fractions < or = 35% to 40% in retrospective studies. The results of two small prospective randomized trials also show significant survival advantage as compared with those for type-1C drugs and a mixed group of antiarrhythmic drugs. An initial strategy of ICD therapy was shown to be superior in the Netherlands Cooperative Study. The 30-day perioperative mortality rate of ICD therapy of 0.8% contrasts favorably with a 13% mortality rate in the ESVEM trial with antiarrhythmic drugs and a 3.5% mortality rate in the CASCADE study. Economic analyses show that drug therapy and device therapy are both within the range of other current cardiovascular therapies. An improving economic profile for device therapy has been observed with nonthoracotomy and pectoral implantation and direct use of ICD therapy because primary therapy shortens hospital stay and reduces costs. Based on available data, ICD therapy is preferable as initial therapy in patients with malignant ventricular tachyarrhythmias.

Sonographic signs in portal hypertension: a multivariate analysis.

A prospective case controlled study was conducted to evaluate the value of real time ultrasound in establishing the diagnosis and the etiology of portal hypertension. Patients attending the outpatient department of a tertiary care centre were included. There were 324 consecutive patients with portal hypertension due to cirrhosis (n = 229), non cirrhotic portal fibrosis (NCPF: n = 64) and extrahepatic portal venous obstruction (EHPVO: n = 31). During this period, 146 patients with dyspepsia, 35 with splenomegaly and 32 with ascites due to varied causes served as negative and positive controls. Real time ultrasonography using a 3.5 MHz linear array scanner was performed in a fasting state in all subjects. Portal and splenic vein diameter greater than 10 mm, splenomegaly, hepatic and splenic hilar collaterals were suggestive of portal hypertension. Non visualization of the portal vein which was replaced by a cavernoma had a diagnostic accuracy of 98% in EHPVO. Splenic infarcts and absence of ascites were features of non cirrhotic portal hypertension (NCPF and EHPVO). Sonography had an overall diagnostic accuracy of 80%. A stepwise logistic regression with multivariate analysis using discriminate function showed that collaterals at the hepatic and splenic hilum, hepatomegaly, ascites and splenic infarcts were independent markers to differentiate cirrhotic from noncirrhotic causes of portal hypertension. The discriminate equation generated had a mismatch of 9.8%. Correlations between the sonographic signs demonstrated that the variceal grade correlated positively with the presence of splenic hilar collaterals and the liver size inversely correlated with presence of ascites. It was concluded that real time ultrasonography is an accurate method to establish the presence and etiology of portal hypertension.

Histopathological changes following laser ablation of a left-sided accessory pathway in a human.

Laser ablation was performed intraoperatively in a patient with coronary artery disease and Wolff-Parkinson-White syndrome. Histopathological evaluation of the laser ablation site revealed a transverse laser incision in the left atrial septum and mitral valve annulus. There was hemorrhage in the atrioventricular (AV) groove with interruption of a posterolateral AV connection. The laser lesion was confined largely to the atrial aspect of the AV annulus. We conclude that laser catheter ablation of accessory pathways is feasible in humans.

Dual isolation technique for paediatric lung surgery.

This report describes a dual isolation technique adopted to isolate the lungs from one another at the time of right pneumonectomy in a child (age: 5 yrs, 10 kg weight) with evidence of infective lung disease associated with copious purulent secretion and compromised respiratory function. The isolation of right lung from left was achieved by placing Fogarty embolectomy catheter in right main bronchus and a plain polyvinylchloride endotracheal tube (which was aseptically preshaped to have a distal 45 degrees angulation towards left) in left main bronchus. No soiling of left lung occurred during surgery and patient remained hemodynamically stable. In the same child, post-thoracotomy pain was relieved for five days with buprenorphine, administered through a lumbar epidural catheter. The child had an uneventful post-operative course and cooperated for physiotherapy.

Hypotensive anaesthesia for spine surgery--nitroglycerin vs halothane.

Thirty patients (ASA I or II) requiring spine surgery under general anesthesia were studied. To induce hypotension, halothane 0.5 to 2.5% (n = 15) or nitroglycerin infusion (1-2 micrograms/kg/min) (n = 15) was used. The parameters studied were blood pressure, blood loss, operating time and recovery score. The systolic blood pressure was maintained between 80-100 mmHg during surgery in both the groups. The blood loss with nitroglycerin was significantly less (202 +/- 114 ml) than halothane group (602 +/- 312 ml). All the patients were alert at the end of surgery in the nitroglycerin group (recovery score 9.8 +/- 0.76) as against the halothane group (7.98 +/- 0.9 p < 0.01). Tachycardia or tachyphylaxis was not observed with nitroglycerin. This study suggests that continuous intravenous infusion of nitroglycerin is effective and safe in reducing blood loss and operating time during spine surgery.

Device use patterns and clinical outcome of implantable cardioverter defibrillator patients with moderate and severe impairment of left ventricular function.

The beneficial effects of implanted cardioverter defibrillator (ICD) therapy in patients with malignant ventricular tachyarrhythmias and variable degrees of left ventricular (LV) dysfunction are debated. ICD use and patient survival were examined in 128 patients with malignant ventricular arrhythmias and moderate or severe LV dysfunction. Group I included 64 patients with moderate LV dysfunction (LV ejection fraction of > 30%) and group II, 64 patients with severe LV dysfunction (LV ejection fraction of < or = 30%). Follow-up period ranged from 1 to 78 months. The two groups were similar in age, incidence of coronary artery disease and presenting arrhythmia. The mean LV ejection fraction in group I was 44% +/- 8% and group II was 22% +/- 5% (P < 0.0001). At 4 years of follow-up, 66% of patients from group I and 62% from group II (P = NS) had ICD activation for presumed ventricular tachyarrhythmia. Survival was calculated using actuarial analysis. Arrhythmic or sudden death mortality at 4 years of follow-up was 4% in group I and 7% in group II (P = NS). Cardiac mortality was for group I, 7% (P < 0.05), 12% (P < 0.01), 15% (P < 0.01), and 15% (P < 0.01) for follow-up years 1, 2, 3, and 4, respectively. For group II, cardiac mortality was 27%, 36%, 41%, and 41% for follow-up years for 1, 2, 3, and 4, respectively. The majority of cardiac deaths in both groups was observed in the first 2 years of follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)

Survival of implantable cardioverter-defibrillator recipients: role of left ventricular function and its relationship to device use.

The quantitative benefit of ICD therapy in patients with malignant ventricular tachyarrhythmia with different degrees of left ventricular dysfunction is unclear. We evaluated patterns of ICD use and survival in 112 patients with moderate to severe left ventricular dysfunction. Group 1 included 57 patients with moderate left ventricular dysfunction (defined as left ventricular ejection fraction greater than 30%) and group 2 comprised 55 patients with severe left ventricular dysfunction (defined as ejection fraction equal to or less than 30%). The follow-up period ranged from 1 to 78 months. Age, incidence of coronary artery disease, and presenting arrhythmia in the two groups were similar. The mean left ventricular ejection fraction in group 1 was 44.6 +/- 8.2% and in group 2 was 21.6 +/- 6% (p < 0.0001). At 3 years of follow-up 65% of the patients in group 1 and 71% in group 2 (p = NS) had ICD activation for presumed ventricular tachycardia. Survival was calculated by means of actuarial analysis. Arrhythmia or sudden death mortality at 4 years of follow-up was 5% in group 1 and 9% in group 2 (NS). Cardiac mortality was higher in patients with severe left ventricular dysfunction reaching levels of statistical significance at 2 years of follow-up. At 2 years of follow-up it was 12% in group 1 and 40% in group 2 (p = 0.05), and at 4 years of follow-up it was 15% in group 1 and 43% in group 2 (p < 0.01). In both groups there was no difference in cardiac mortality in patients who did and did not have appropriate ICD shocks.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term multicenter experience with a second-generation implantable pacemaker-defibrillator in patients with malignant ventricular tachyarrhythmias. The Guardian Multicenter Investigators Group.

A second-generation implantable pacemaker-cardioverter-defibrillator was evaluated in 200 patients with sustained ventricular tachycardia, ventricular fibrillation or prior cardiac arrest. The device permits demand ventricular pacing for bradyarrhythmias and for long QT interval or tachycardia suppression, uses programmable (3 to 30 J) energy shocks for conversion of ventricular tachycardia and ventricular fibrillation and is used with conventional pacing and defibrillation leads. Ventricular tachycardia/fibrillation recognition is based on the ventricular electrogram rate and requires reconfirmation before shock delivery. Two hundred patients (mean age 62 years, mean left ventricular ejection fraction 36%) were enrolled and followed up for 0 to 23 months (mean 12). Epicardial lead system implantation was performed with use of an anterolateral thoracotomy (38%), median sternotomy (26%) and subxiphoid (20%) or subcostal (16%) approach. Perioperative mortality rate was 5.5% (all nonarrhythmic deaths). Implant defibrillation threshold ranged from 3 to 30 J (mean 15), with initial programmed shock energy ranging from 3 to 30 J (mean 22). Ventricular tachycardia/fibrillation sensing threshold ranged from 0.7 to 1.8 mV (median 1) and the tachycardia detection interval from 288 to 416 ms (median 320). Reprogramming of implant variables was necessary for reliable electrographic sensing (54 patients), programmed shock therapy (61 patients) and tachycardia detection rate (63 patients). Device activation for potential shock delivery occurred in 111 patients (55.5%) with actual shock delivery after ventricular tachycardia/fibrillation reconfirmation in 66 patients (33%). During follow-up study, there was a 1% arrhythmia mortality rate, 6.5% cardiac mortality rate and 10.5% total mortality rate. This study demonstrates that the programmable implantable pacemaker-cardioverter-defibrillator is effective in preventing arrhythmic death, yet reduces patient exposure to repeated shock therapy. Reprogramming is usually necessary during follow-up for optimal function.