Putting patients at the center of kidney care transitions: PREPARE NOW, a cluster randomized controlled trial.

Care for patients transitioning from chronic kidney disease to kidney failure often falls short of meeting patients' needs. The PREPARE NOW study is a cluster randomized controlled trial studying the effectiveness of a pragmatic health system intervention, 'Patient Centered Kidney Transition Care,' a multi-component health system intervention designed to improve patients' preparation for kidney failure treatment. Patient-Centered Kidney Transition Care provides a suite of new electronic health information tools (including a disease registry and risk prediction tools) to help providers recognize patients in need of Kidney Transitions Care and focus their attention on patients' values and treatment preferences. Patient-Centered Kidney Transition Care also adds a 'Kidney Transitions Specialist' to the nephrology health care team to facilitate patients' self-management empowerment, shared-decision making, psychosocial support, care navigation, and health care team communication. The PREPARE NOW study is conducted among eight [8] outpatient nephrology clinics at Geisinger, a large integrated health system in rural Pennsylvania. Four randomly selected nephrology clinics employ the Patient Centered Kidney Transitions Care intervention while four clinics employ usual nephrology care. To assess intervention effectiveness, patient reported, biomedical, and health system outcomes are collected annually over a period of 36 months via telephone questionnaires and electronic health records. The PREPARE NOW Study may provide needed evidence on the effectiveness of patient-centered health system interventions to improve nephrology patients' experiences, capabilities, and clinical outcomes, and it will guide the implementation of similar interventions elsewhere. TRIAL REGISTRATION: NCT02722382.

The role of the defaecating pouchogram in the assessment of evacuation difficulty after restorative proctocolectomy and pouch-anal anastomosis.

AIM: Restorative proctocolectomy (RPC) with ileal pouch-anal anastomosis (IPAA) is the most frequently performed operation for intractable ulcerative colitis (UC) and for many patients with familial adenomatous polyposis (FAP). It can be complicated by a functional evacuation difficulty, which is not well understood. We aimed to evaluate the role of defaecating pouchography in an attempt to assess the mechanism of evacuation difficulty in pouch patients. METHOD: All RPC patients who had had a defaecating pouchogram for evacuation difficulty at one hospital between 2006 and 2014 were retrospectively reviewed. The findings and features were correlated with the symptoms. Demographic, clinical and radiological variables were analysed. RESULTS: Eighty-seven [55 (63%) female] patients aged 47.6 ± 12.5 years (mean standard ± SD) were identified. Thirty-five had a mechanical outlet obstruction and 52 had no identified mechanical cause to explain the evacuation difficulty. The mean age of these 52 [33 (63%) female] patients was 48.2 ± 13 years. Of these 52 patients, significantly more used anti-diarrhoeal medication (P = 0.029), complained of a high frequency of defaecation (P = 0.005), experienced a longer time to the initiation of defaecation (P = 0.049) and underwent pouchoscopy (P = 0.003). Biofeedback appeared to improve the symptoms in 7 of 16 patients with a nonmechanical defaecatory difficulty. The most common findings on defaecating pouchography included residual barium of more than 33% after an attempted evacuation (46%, n = 24), slow evacuation (35%, n = 18) and mucosal irregularity (33%, n = 17). Correlation between radiological features and symptoms showed a statistically significant relationship between straining, anal pain, incontinence and urgency with patterns of anismus or pelvic floor descent or weakness seen on the defaecating pouchogram. Symptoms of incomplete evacuation, difficulty in the initiation of defaecation, high defaecatory frequency and abdominal pain were not correlated with the radiological features of the pouchogram. CONCLUSION: Defaecating pouchography may be useful for identifying anismus and pelvic floor disorders in pouch patients who have symptoms of straining, anal pain or incontinence. In patients with a high frequency of defaecation and abdominal pain it does not provide clinically meaningful information. Patients who complain of straining, incontinence, anal pain or urgency and have anismus or pelvic floor disorders may benefit from behavioural therapy.

Cardioprotective effect of Saraca indica against cyclophosphamide induced cardiotoxicity in rats: a biochemical, electrocardiographic and histopathological study.

OBJECTIVES: Cardioprotective activity of alcoholic extract of Saraca indica (SI) bark was investigated against cyclophosphamide induced cardiotoxicity. MATERIALS AND METHODS: Cardiotoxicity was induced in Wistar rats by administering cyclophosphamide (200 mg/kg, i.p.) single injection on first day of experimental period. Saraca indica (200 and 400 mg/kg, p.o.) was administered immediately after administration of cyclophosphamide on first day and daily for 10 days. The general observations and mortality were measured. RESULTS: Cyclophosphamide administration significantly (p < 0.05) increased lipid peroxidation (LPO) and decreased the levels of antioxidant markers such as reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT). Cyclophosphamide elevated the levels of biomarker enzymes like creatine kinase (CK), creatine kinase isoenzyme MB (CK-MB), lactate dehydrogenase (LDH), aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP). Further, the cyclophosphamide treated rats showed changes in electrocardiogram (ECG) along with increased levels of cholesterol and triglycerides. Treatment with Saraca indica significantly (p < 0.05) reversed the status of cardiac biomarkers, ECG, oxidative enzymes and lipid profile in cyclophosphamide induced cardiotoxicity. Potential cardioprotective effect of Saraca indica was supported by histopathological examination that reduced severity of cellular damage of the myocardium. CONCLUSION: The biochemical, ECG and histopathology reports support the cardioprotective effect of Saraca indica which could be attributed to antioxidant activity.

Evaluation of Diuretic Activity of Aqueous and Methanol Extracts of Lepidium sativum Garden Cress (Cruciferae) in Rats

Purpose: The present study was undertaken to investigate diuretic effect of aqueous and methanol extracts of the dried seeds of Lepidium sativum in normal rats. Method: Aqueous and methanol extracts of L. sativum seeds were administered to experimental rats orally at doses of 50 and 100 mg/kg p.o. Hydrochlorothiazide (10 mg/kg) was used as positive control in study. The diuretic effect of the extracts was evaluated by measuring urine volume; sodium and potassium content; conductivity and pH. Result: Urine volume was significantly increased by the two doses of aqueous and methanol extracts in comparison to control group. While the excretion of sodium was also increased by both extracts; potassium excretion was only increased by the aqueous extract at a dose of 100 mg/kg. There was no significant change in the conductivity and pH of urine after administration of the L. sativum extracts. The diuretic effect of the extracts was comparable to that of the reference standard (hydrochlorothiazide) and the methanol had the additional advantage of a potassium-conserving effect. Conclusion: We can conclude that aqueous and methanol extracts of L. sativum produced notable diuretic effect which appeared to be comparable to that produced by the reference diuretic HCTZ. The present study provides a quantitative basis for explaining the folkloric use of L. sativum as a diuretic agent in Moroccan population

Identification of inhibitors of bacterial transcription/translation machinery utilizing a miniaturized 1536-well format screen.

This report presents the miniaturization of a HTS screen to identify inhibitors of prokaryotic transcription-translation in a 1536-well format. The in vitro assay design utilized the bacterial expression machinery to drive expression of a firefly luciferase reporter gene, which was read as an endpoint luminesence measurement. This multicomponent system permits identification of inhibitors at different steps in this pathway. Successful miniaturization required integration of homogeneous assay formats, robust liquid-handling workstations, and second-generation imaging systems. Comparison of data from a triplicate 1536-well screen of a subset of a target library that had been previously validated and followed up for hit confirmation in a 384-well plate format confirmed that triplicate screening yields data of higher confidence and quality, eliminates the time-consuming and potentially error-prone step of cherry-picking, and reduces the number of false positives and negatives. The substantial savings of reagents and reduction of the numbers of plates to process obtained in a 1536-well format as compared to a 384-well format allowed a full triplicate evaluation of the entire library of 183,000 compounds at lower cost and in less time. The triplicate-screen statistics are consistent with a highly reliable data set with a coefficient of variation of 14.8% and Z' and Z values of 0.57 and 0.25, respectively. This screen resulted in the identification of 1,149 hits (0.63% hit rate), representing a compound population at 2.5 standard deviations from the mean cutoff. Furthermore, the data demonstrate good agreement between IC(50) values derived for this assay in a 1536-well format and 384-well format.

Rapid conversion of tea catechins to monomethylated products by rat liver cytosolic catechol-O-methyltransferase.

1. The metabolic O-methylation of several catechol-containing tea polyphenols by rat liver cytosolic catechol-O-methyltransferase (COMT) has been studied. 2. When (-)-epicatechin was used as substrate, its O-merthylation showed dependence on incubation time, cytosolic protein concentration, incubation pH and concentration of S-adenosyl-L-methionine. The O-methylation of increasing concentrations of (-)-epicatechin followed typical Michaelis-Menten kinetics, and the apparent Km and Vmax were 51 microM and 2882 pmol mg protein(-1) min(-1), respectively, at pH 7.4, and were 17 microM and 2093 pmol mg protein(-1) min(-1), respectively, at pH 10.0. 3. Under optimized conditions for in vitro O-methylation, (-)-epicatechin, (+)-epicatechin and (-)-epigallocatechin were rapidly O-methylated by rat liver cytosol. In comparison, (-)-epicatechin gallate and (-)-epigallocatechin gallate vere O-methylated at significantly lower rates under the same reaction conditions. catalysed O-methylation of (-)-epicatechin and (-)-epigallocatechin was inhibited in a concentration-dependent manner by S-adenosyl-L-homocysteine, a demethylated product of S-adenosyl-L-methionine. The IC50 was approximately 10 microM. 5. In summary, the results showed that several catechol-containing tea polyphenols were rapidly O-methylated by rat liver cytosolic COMT. These observations raise the possibility that some of the biological effects of tea polyphenols may be exerted by their O-methylated products or may result from their potential inhibition of the COMT-catalysed O-methylation of endogenous catecholamines and catechol oestrogens.

O-Methylation of tea polyphenols catalyzed by human placental cytosolic catechol-O-methyltransferase.

In the present study, we evaluated the metabolic O-methylation of several catechol-containing tea polyphenols by human placental catechol-O-methyltransferase (COMT). (-)-Epicatechin, (+)-epicatechin, and (-)-epigallocatechin were good substrates for metabolic O-methylation by placental cytosolic COMT (150-500 pmol/mg of protein/min), but (-)-epicatechin gallate and (-)-epigallocatechin gallate were O-methylated at much lower rates (<50 pmol/mg of protein/min). When (-)-epicatechin was used as substrate, its O-methylation by human placental COMT showed dependence on incubation time, cytosolic protein concentration, incubation pH, and concentration of S-adenosyl-L-methionine (the methyl donor). Analysis of cytosolic COMT from six human term placentas showed that the O-methylation of increasing concentrations of (-)-epicatechin or (-)-epigallocatechin follows typical Michaelis-Menten kinetics, with K(m) and V(max) values of 2.2 to 8.2 microM and 132 to 495 pmol/mg of protein/min for (-)-epicatechin and 3.9 to 6.7 microM and 152 to 310 pmol/mg of protein/min for (-)-epigallocatechin, respectively. Additional analysis revealed that COMT-catalyzed O-methylation of (-)-epicatechin and (-)-epigallocatechin was strongly inhibited in a concentration-dependent manner by S-adenosyl-L-homocysteine (IC(50) = 3.2-5.7 microM), a demethylated product of S-adenosyl-L-methionine. This inhibition by S-adenosyl-L-homocysteine follows a mixed (competitive plus noncompetitive) mechanism of enzyme inhibition. In summary, several catechol-containing tea polyphenols are rapidly O-methylated by human placental cytosolic COMT. This metabolic O-methylation is subject to strong inhibitory regulation by S-adenosyl-L-homocysteine, which is formed in large quantities during the O-methylation of tea polyphenols.

Recombinant soluble form of PSGL-1 accelerates thrombolysis and prevents reocclusion in a porcine model.

BACKGROUND: We investigated whether administration of a soluble recombinant P-selectin glycoprotein ligand-1 chimera (rPSGL-Ig) in conjunction with thrombolytic therapy would enhance thrombolysis by preventing ongoing interactions of leukocytes with platelets and the injured arterial wall. METHODS AND RESULTS: An occlusive thrombus was formed in an internal iliac artery of Yorkshire pigs by placement of a copper coil in the artery under fluoroscopic guidance. Pigs then received heparin and, 15 minutes later, either vehicle or rPSGL-Ig followed by infusion with 25 mg tissue plasminogen activator according to the 90-minute regimen. Blood flow through the artery was monitored by angiography and scored on a scale of 0 to 3. Lysis of the thrombus was accelerated by 70% in pigs treated with rPSGL-Ig 250 microg/kg compared with control (13.3+/-5.0 versus 44. 4+/-13.3 minutes; n=9 each). Eight of 9 control pigs reoccluded in 13.8+/-16.9 minutes after the end of tissue plasminogen activator infusion, whereas no reocclusion was observed in 8 of 9 pigs in the rPSGL-Ig group. When the dose of rPSGL-Ig was increased to 500 microg/kg, time to lysis was shortened by 61% from control (18.0+/-8. 4 versus 46.0+/-8.9 minutes). Reocclusion occurred in 6.0+/-15.2 minutes in control but not in any rPSGL-Ig-treated pig (n=5 each). In addition, near-normal flow (score 2 or 3) after thrombolysis was achieved 59% and 58% faster in the 2 rPSGL-Ig groups than in their respective controls. CONCLUSIONS: Inhibition of leukocyte accumulation at the site of thrombosis with rPSGL-Ig may represent a safe therapeutic intervention that could be important in accelerating thrombolysis, achieving optimal reperfusion, and reducing incidence of acute reocclusion.

MR imaging of the mamillothalamic tract.

PURPOSE: To demonstrate the normal and abnormal appearance of the mamillothalamic tract (MTT) on cranial magnetic resonance (MR) images. MATERIALS AND METHODS: Two formalin-fixed normal human brain specimens sectioned in axial and coronal planes were used to demonstrate the normal anatomy of the MTT. MR images were obtained in 32 volunteers. Proton-density-weighted coronal and axial pulse sequences were used. The images were evaluated for visualization quality and size and signal intensity of the MTTs in correlation with the specimens. Abnormal MTTs were identified on cranial MR images in two patients, and the imaging findings were analyzed. The clinical history of the patients was also reviewed to determine the effect of these findings on patient care. RESULTS: Normal MTTs were easily identified on MR studies of cadaveric brains and of the brains of the human volunteers. On MR images, normal MTTs were commonly symmetric in appearance, with signal intensity equal to that of other normal fiber tracts. The abnormal MTTs showed high signal intensity on images obtained with a long repetition time or asymmetric volume loss and were associated with atrophy of the ipsilateral mamillary body. CONCLUSION: Normal MTTs are readily visible on conventional MR images. Abnormality of the MTT is a very subtle finding but may be a marker of a limbic system abnormality.

Development of a rapidly computable descriptor of prostate tissue temperature during transurethral conductive heat therapy for benign prostate hyperplasia.

Benign prostate hyperplasia (BPH) is a condition in older men in which the mass of tissue in the prostate gland gradually increases over the course of many years, ultimately leading to urinary outflow obstruction. Current treatment of this condition is to surgically remove the obstructing tissue. One novel alternative therapy being studied is transurethral thermocoagulation of excessive prostatic mass. In this approach, a heat-emitting catheter is placed in the prostatic urethra, and the intraprostatic segment of the catheter is heated to temperatures above 60 degrees C for one hour. Two-dimensional cylindrical-co-ordinate computer simulations of this treatment modality were run to model resultant temperature distributions within the prostate gland and surrounding tissues. The simulations revealed that resultant tissue temperature changes were related directly to the power delivered to the catheter and inversely to the rate of blood perfusion. Further analysis of the temperature profiles produced a rapidly computable predictor of tissue temperature in the radial dimension. Using the predictor, a 'kill radius' around the prostatic urethra can be easily computed on-line, during treatment, from clinically available data, catheter power and catheter temperature. The computed kill radius may serve as a useful predictor of the extent of thermal devitalization of unwanted obstructing tissue and the long-term success of the treatment in relieving urinary outflow obstruction without surgery.

Utility of the instant (unprepared) enema in Crohn's colitis.

Thirty-seven instant (unprepared) barium enemas in 30 patients with proven Crohn's colitis were reviewed. Plain films in 28 indicated that confluence or discontinuity of the colitis did not substantially alter the pattern of faecal residue. In only one patient was residue found overlying active mucosal disease. Aphthoid ulceration was demonstrated in 27%. In five (13%) examinations the colitis was granular and indistinguishable from ulcerative colitis. In 26/37 (70%) typical stigmata of Crohn's colitis were present. There was no complication or clinical deterioration after the instant enema. The instant enema was found to be comparable to a prepared examination for the diagnosis of advanced Crohn's disease, though less accurate for demonstrating early changes.

Droop: a rapidly computable descriptor of local minimum tissue temperature during conductive interstitial hyperthermia.

Although the goal of local hyperthermia therapy for cancer is to elevate the temperature of a tumour to cytotoxic levels, without the presence of 'cold spots', varying blood flow has made the achievement of consistent, therapeutic temperature distributions extraordinarily difficult. The paper presents a novel approach to estimating local minimum tumour temperatures during conductive interstitial hyperthermia which facilitates identification and elimination of cold spots. Conductive interstitial hyperthermia is modelled mathematically for a parallel array of implanted, electrically heated catheters which warms the treated tissue by thermal conduction and blood perfusion. Computer simulations employing the bioheat transfer equation reveal a predictive relationship between implanted catheter temperature, catheter power, implantation geometry and local minimum tumour temperature. Formulation of this relationship in terms of a parameter named 'droop' allows estimation of local minimum intratumoural temperatures from individual catheter temperature and power. Computer simulations are also performed to determine the sensitivity of the droop-based estimator to variations in properties of the tissue and catheters. Generally, variations in geometry or thermal properties of about 10 per cent cause estimation errors of less than 1 degree C in magnitude. These results suggest that online estimates of thermal 'droop' may provide a practical route to more consistent control of intratumoural minimum temperature during conductive interstitial heat therapy.

Effective estimation and computer control of minimum tumour temperature during conductive interstitial hyperthermia.

The goal of heat therapy in the treatment of malignant disease is to raise the temperature of all neoplastic tissue to a cytotoxic temperature for a predetermined period of time. This seemingly simple task has proved difficult in vivo in part because of non-uniform power absorption and in part because of non-homogeneous and time-varying tumour blood flow. We have addressed this difficulty first by utilizing the conceptually simple technique of conductive interstitial hyperthermia, in which the tumour is warmed by multiple, electrically heated catheters, and second by implementing on-line control of minimum tumour temperatures near each catheter, estimated on the basis of the steady-state ratio of catheter power to catheter temperature rise. This report presents an analysis of the accuracy, precision, and stability of the on-line minimum temperature estimation/control technique for 22 patients who received 31 separate courses of conductive interstitial hyperthermia for the treatment of malignant brain tumours, and in whom temperature was monitored independently by 12-16 independent sensors per patient. In all patients the technique was found to accurately and precisely estimate and control the local minimum temperatures. Comparison of measured and estimated temperatures revealed a mean difference of 0.0 +/- 0.4 degrees C for those sensors within 1.0 mm of the expected location for minimum temperatures. This technique therefore offers an attractive method for controlling hyperthermia therapy-even in the presence of time varying local blood flow.

Design and evaluation of closed-loop feedback control of minimum temperatures in human intracranial tumours treated with interstitial hyperthermia.

The dynamic nature of blood flow during hyperthermia therapy has made the control of minimum tumour temperature a difficult task. The paper presents initial studies of a novel approach to closed-loop control of local minimum tissue temperatures utilising a newly developed estimation algorithm for use with conductive interstitial heating systems. The local minimum tumour temperature is explicitly estimated from the power required to maintain each member of an array of electrically heated catheters at a known temperature, in conjunction with a new bioheat equation-based algorithm to predict the 'droop' or fractional decline in tissue temperature between heated catheters. A closed loop controller utilises the estimated minimum temperature near each catheter as a feedback parameter, which reflects variations in local blood flow. In response the controller alters delivered power to each catheter to compensate for changes in blood flow. The validity and stability of this estimation/control scheme were tested in computer simulations and in closed-loop control of nine patient treatments. The average estimation error from patient data analysis of 21 sites at which temperature was independently measured (three per patient) was 0.0 degree C, with a standard deviation of 0.8 degree C. These results suggest that estimation of local minimum temperature and feedback control of power delivery can be employed effectively during conductive interstitial heat therapy of intracranial tumours in man.

Computer-aided design and evaluation of novel catheters for conductive interstitial hyperthermia.

Conductive interstitial heating is a modality in which heating elements are implanted directly into the treated tissue. One implementation of such therapy employs electrically heated catheters that are implanted in staggered, parallel rows. To explore strategies for maximising the uniformity of tissue temperature distributions achieved with heated catheters, a two-dimensional computer model with cylindrical co-ordinates was used to evaluate radially and longitudinally the temperature distributions produced by a typical interior catheter surrounded by other similar catheters. Insights from the computer model led to new designs for catheters containing multiple heating elements that produced more uniform thermal distributions, eliminating previous 'cold spots' within the treatment volume located near the ends of the catheter. The new catheter designs also include compartments for the optional placement of radioactive seeds for simultaneous thermoradiotherapy.

Cancer-associated hypercalcemia: morbidity and mortality. Clinical experience in 126 treated patients.

STUDY OBJECTIVE: To review the effects of antihypercalcemic treatment on morbidity and mortality in cancer-associated hypercalcemia. DESIGN: Retrospective study of 126 consecutive patients with cancer-associated hypercalcemia. SETTING: Inpatient referrals from a teaching hospital in the United Kingdom. INTERVENTION: Medical antihypercalcemic therapy supplemented by specific anticancer therapy where possible. MEASUREMENTS AND MAIN RESULTS: Median survival was 30 days. Survival did not differ in patients treated with different antihypercalcemic regimens but was longer (median, 135 days; P less than 0.001) in a subgroup of 26 patients for whom specific anticancer therapy was available. Polyuria and polydipsia improved after therapy in 83% of cases, central nervous system symptoms in 71%, constipation in 70%, nausea and vomiting in 56%, anorexia in 50%, and malaise and fatigue in 47% (all significant, P less than 0.001, pre-treatment compared with post-treatment). Pain control improved in only 23% of cases (not significant). Only 7% of patients with post-treatment serum calcium values above 3.50 mmol/L improved clinically compared with 80% whose calcium values fell below 2.80 mmol/L (P less than 0.001). Corresponding figures for the proportion of patients discharged from the hospital were 0% and 68% (P less than 0.001). CONCLUSIONS: Life expectancy is poor in cancer-associated hypercalcemia even in patients who are actively treated. Antihypercalcemic therapy has an important palliative role, however, because symptoms are usually improved and, in many cases, patients may be made well enough to be discharged from the hospital during the terminal stages of their illness.

Regional differences in cell density and cell genesis in the olfactory epithelium of the salamander, Ambystoma tigrinum.

The olfactory epithelium undergoes continuous regeneration. The present quantitative study uses tritiated thymidine autoradiography to investigate regional differences in the rate of olfactory epithelial cell genesis in the tiger salamander. There was a significant gradient in the incorporation of thymidine from the posterior to the anterior in the nasal cavity: the posterior epithelium underwent cell genesis much faster than the anterior. Additionally, the posterior epithelium was thinner and contained fewer cells than the anterior, although the proportions of receptor, supporting and basal cells remained about the same throughout the epithelium. After 5 or 20 days most of the labelled cells were found in the basal cell layer, although there were a few labelled supporting cells. This confirms observations in other species that there are two populations of dividing cells in the olfactory epithelium: the basal cells which give rise to receptor cells, and the supporting cells. The gradients in epithelial thickness, receptor cells, and the rate of cell genesis parallel a gradient in responsiveness to odorants observed in electrophysiological studies (Mackay-Sim et al. 1982; Mackay-Sim and Shaman 1984). The significance of these anatomical and physiological gradients is presently unclear.