Design, synthesis, and biological evaluation of aryl piperazines with potential as antidiabetic agents via the stimulation of glucose uptake and inhibition of NADH:ubiquinone oxidoreductase.

The management of blood glucose levels and the avoidance of diabetic hyperglycemia are common objectives of many therapies in the treatment of diabetes. An aryl piperazine compound 3a (RTC1) has been described as a promoter of glucose uptake, in part through a cellular mechanism that involves inhibition of NADH:ubiquinone oxidoreductase. We report herein the synthesis of 41 derivatives of 3a (RTC1) and a systematic structure-activity-relationship study where a number of compounds were shown to effectively stimulate glucose uptake in vitro and inhibit NADH:ubiquinone oxidoreductase. The hit compound 3a (RTC1) remained the most efficacious with a 2.57 fold increase in glucose uptake compared to vehicle control and micromolar inhibition of NADH:ubiquinone oxidoreductase (IC50 = 27 µM). In vitro DMPK and in vivo PK studies are also described, where results suggest that 3a (RTC1) would not be expected to provoke adverse drug-drug interactions, yet be readily metabolised, avoid rapid excretion, with a short half-life, and have good tissue distribution. The overall results indicate that aryl piperazines, and 3a (RTC1) in particular, have potential as effective agents for the treatment of diabetes.

Outcomes after implementation of a multimodal standard care pathway for laparoscopic colorectal surgery.

BACKGROUND: The aim of the study was to assess which aspects of an enhanced recovery programme are associated with better outcomes following laparoscopic colorectal surgery. METHODS: A database of laparoscopic colorectal procedures performed in 2011 was reviewed. Elements of the enhanced recovery programme and compliance were evaluated for short-term (30-day) outcomes. Individual elements included gabapentin, celecoxib, intrathecal analgesia, diet, postoperative fluids, and paracetamol/non-steroidal anti-inflammatory drug pain management. RESULTS: Five hundred and forty-one consecutive procedures were included. Compliance with the enhanced recovery programme elements ranged from 82.4 to 99.3 per cent. Median length of hospital stay was 3 (i.q.r. 2-5) days, with 25.9 per cent of patients discharged within 48 h. Patients without complications had a median length of stay of 3 (i.q.r. 2-4) days if compliant and 3 (3-5) days if not (P < 0.001). Low oral opiate intake (oral morphine equivalent of less than 30 mg) (odds ratio (OR) 1.97, 95 per cent confidence interval 1.29 to 3.03; P = 0.002), full compliance (OR 2.36, 1.42 to 3.90; P < 0.001) and high surgeon volume (more than 100 cases per year) (OR 1.50, 1.19 to 1.89; P < 0.001) were associated with discharge within 48 h. Compliance with the elements of oral intake and fluid management in the first 48 h was associated with a reduced rate of complications (8.1 versus 19.6 per cent; P = 0.001). Median oral opiate intake was 37.5 (i.q.r. 0-105) mg in 48 h, with 26.2 per cent of patients receiving no opiates. CONCLUSION: Compliance with an enhanced recovery pathway was associated with less opiate use, fewer complications and a shorter hospital stay.

Malignant risk and surgical outcomes of presacral tailgut cysts.

BACKGROUND: Presacral tailgut cysts are uncommon and few data exist on the outcomes following surgery. METHODS: Patients undergoing tailgut cyst resection at the Mayo Clinic between 1985 and 2008 were analysed retrospectively. Demographic data, clinicopathological features, operative details, postoperative complications and recurrence were reviewed. RESULTS: Thirty-one patients were identified (28 women), with a median age of 52 years. Seventeen patients were symptomatic and 28 had a palpable mass on digital rectal examination. Median cyst diameter was 4.4 cm. Four patients had a fistula to the rectum. Complete cyst excision was achieved in all patients; eight underwent distal sacral resection or coccygectomy. Postoperative complications occurred in eight patients but without 30-day mortality. Malignant transformation was present in four patients: adenocarcinoma in three and carcinoid in one. The cyst recurred in one patient after surgery for a benign lesion. CONCLUSION: Presacral tailgut cysts should be removed due to the risk of malignant transformation.

Personal dose equivalent conversion coefficients for neutron fluence over the energy range of 20-250 MeV.

Monte Carlo simulations were performed to extend existing neutron personal dose equivalent fluence-to-dose conversion coefficients to an energy of 250 MeV. Presently, conversion coefficients, H(p,slab)(10,alpha)/Phi, are given by ICRP-74 and ICRU-57 for a range of angles of radiation incidence (alpha = 0, 15, 30, 45, 60 and 75 degrees ) in the energy range from thermal to 20 MeV. Standard practice has been to base operational dose quantity calculations <20 MeV on the kerma approximation, which assumes that charged particle secondaries are locally deposited, or at least that charged particle equilibrium exists within the tally cell volume. However, with increasing neutron energy the kerma approximation may no longer be valid for some energetic secondaries such as protons. The Los Alamos Monte Carlo radiation transport code MCNPX was used for all absorbed dose calculations. Transport models and collision-based energy deposition tallies were used for neutron energies >20 MeV. Both light and heavy ions (HIs) (carbon, nitrogen and oxygen recoil nuclei) were transported down to a lower energy limit (1 keV for light ions and 5 MeV for HIs). Track energy below the limit was assumed to be locally deposited. For neutron tracks <20 MeV, kerma factors were used to obtain absorbed dose. Results are presented for a discrete set of angles of incidence on an ICRU tissue slab phantom.

Radiation induced damage and recovery in poly(3-hexyl thiophene) based polymer solar cells.

Polymer solar cells have been characterized during and after x-ray irradiation. The open circuit voltage, dark current and power conversion efficiency show degradation consistent with the generation of defect states in the polymer semiconductor. The polymer solar cell device remained functional with exposure to a considerable dose (500 krad (SiO(2))) and showed clear signs of recovery upon removal of the irradiation source (degraded from 4.1% to 2.2% and recovered to 2.9%). Mobility-relaxation time variation, derived from J-V measurement, clearly demonstrates that radiation induced defect generation mechanisms in the organic semiconductor are active and need to be further studied. Optical transmission results ruled out the possibility of reduced light absorption and/or polymer crystallinity. The results suggest that organic solar cells are sufficiently radiation tolerant to be useful for space applications.

Antimicrobial susceptibilities and clinical sources of Dialister species.

Seventy-four strains representing the four species of the genus Dialister were isolated from various clinical samples. Dialister pneumosintes and Dialister micraerophilus were the two mainly encountered species. Fifty-five isolates were tested against 14 antimicrobial agents. Decreased susceptibilities to piperacillin, metronidazole, macrolides, fluoroquinolones, and rifampin were demonstrated. The clinical impact of these decreased susceptibilities remains to be investigated but should prompt microbiologists to perform antimicrobial susceptibility testing for clinically important Dialister spp.

Characterization of neutron reference fields at US Department of Energy calibration fields.

The Health Physics Measurements Group at the Los Alamos National Laboratory (LANL) has initiated a study of neutron reference fields at selected US Department of Energy (DOE) calibration facilities. To date, field characterisation has been completed at five facilities. These fields are traceable to the National Institute for Standards and Technology (NIST) through either a primary calibration of the source emission rate or through the use of a secondary standard. However, neutron spectral variation is caused by factors such as room return, scatter from positioning tables and fixtures, source anisotropy and spectral degradation due to source rabbits and guide tubes. Perturbations from the ideal isotropic point source field may impact the accuracy of instrument calibrations. In particular, the thermal neutron component of the spectrum, while contributing only a small fraction of the conventionally true dose, can contribute a significant fraction of a dosemeter's response with the result that the calibration becomes facility-specific. A protocol has been developed to characterise neutron fields that relies primarily on spectral measurements with the Bubble Technology Industries (BTI) rotating neutron spectrometer (ROSPEC) and the LANL Bonner sphere spectrometer. The ROSPEC measurements were supplemented at several sites by the BTI Simple Scintillation Spectrometer probe, which is designed to extend the ROSPEC upper energy range from 5 to 15 MeV. In addition, measurements were performed with several rem meters and neutron dosemeters. Detailed simulations were performed using the LANL MCNPX Monte Carlo code to calculate the magnitude of source anisotropy and scatter factors.

CHELSI: a portable neutron spectrometer for the 20-800 MeV region.

CHELSI is a CsI-based portable spectrometer being developed at Los Alamos National Laboratory for use in high-energy neutron fields. Based on the inherent pulse shape discrimination properties of CsI(Tl), the instrument flags charged particle events produced via neutron-induced spallation events. Scintillation events are processed in real time using digital signal processing and a conservative estimate of neutron dose rate is made based on the charged particle energy distribution. A more accurate dose estimate can be made by unfolding the 2D charged particle versus pulse height distribution to reveal the incident neutron spectrum from which dose is readily obtained. A prototype probe has been assembled and data collected in quasi-monoenergetic fields at The Svedberg Laboratory (TSL) in Uppsala as well as at the Los Alamos Neutron Science Center (LANSCE). Preliminary efforts at deconvoluting the shape/energy data using empirical response functions derived from time-of-flight measurements are described.

Operational specifications of the laser illuminated track etch scattering dosemeter reader.

The personnel dosimetry operations team at the Los Alamos National Laboratory (LANL) has accepted the laser illuminated track etch scattering (LITES) dosemeter reader into its suite of radiation dose measurement instruments. The LITES instrument transmits coherent light from a He-Ne laser through the pertinent track etch foil and a photodiode measures the amount of light scattered by the etched tracks. A small beam stop blocks the main laser light, while a lens refocuses the scattered light into the photodiode. Three stepper motors in the current LITES system are used to position a carousel that holds 36 track etch dosemeters (TEDs). Preliminary work with the LITES system demonstrated the device had a linear response in counting foils subjected to exposures up to 50 mSv (5.0 rem). The United States Department of Energy requires that the annual general employee dose not exceed 50 mSv (5.0 rem). On a regular basis, LANL uses the Autoscan-60 reader system (Thermo Electron Corp.) for counting track etch dosemeters. However, LANL uses a 15 h etch process for CR-39 dosemeters, and this produces more and larger track etch pits than the 6 h etch used by many institutions. Therefore, LANL only uses the Autoscan-60 for measuring neutron dose equivalent up to exposure levels of approximately 3 mSv (300 mrem). The LITES system has a measured lower limit of detection of approximately 0.6 mSv (60 mrem), and it has a correlation coefficient of R (2) = 0.99 over an exposure range up to 500 mSv (50.0 rem). A series of blind studies were done using three methods: the Autoscan-60 system, manual counting by optical microscope and the LITES instrument. A collection of track etch dosemeters of unknown neutron dose equivalent (NDE) were analysed using the three methods, and the performance coefficient (PC) was calculated when the NDE became known. The Autoscan-60 and optical microscope methods had a combined PC = 0.171, and the LITES instrument had a PC = 0.194, where a PC less than or equal to 0.300 is considered satisfactory.

Monte Carlo modelling of a simple accident dosemeter.

A simple dosemeter made of a sulphur tablet, bare and cadmium-covered indium foils and a cadmium-covered copper foil has been modelled using MCNP5. Studies of the model without phantom or other confounding factors have shown that the cross sections and fluence-to-dose factors generated by the Monte Carlo method agree with those generated by analytic expressions for the high energy component. In this study, a comparison of the effect of location on phantoms and an extension to low and intermediate energies is done. The activities expected from exposure to four critical assemblies on phantom is calculated and compared with observations.

Monte Carlo modelling of a simple accident dosemeter.

A simple dosemeter made of a sulphur tablet, bare and cadmium-covered indium foils and a cadmium-covered copper foil has been modelled using MCNP5. Studies of the model without phantoms or other confounding factors have shown that the cross sections and fluence-to-dose factors generated by the Monte Carlo method agree with those generated by analytic expressions for the high-energy component. In this study, the effect of location on phantoms is studied and an extension of this study to low and intermediate energies is done. The activities expected from exposure to four critical assemblies on phantom is calculated and compared with observations.

Computation of cross sections and dose conversion factors for criticality accident dosimetry.

In the application of criticality accident dosemeters the cross sections and fluence-to-dose conversion factors have to be computed. The cross section and fluence-to-dose conversion factor for the thermal and epi-thermal contributions to neutron dose are well documented; for higher energy regions (>100 keV) these depend on the spectrum assumed. Fluence is determined using threshold detectors. The cross sections require the folding of an expected spectrum with the reaction cross sections. The fluence-to-dose conversion factors also require a similar computation. The true and effective thresholds are used to include the information on the expected spectrum. The spectra can either be taken from compendia or measured at the facility at which the exposures are to be expected. The cross sections can be taken from data computations or analytic representations and the fluence-to-dose conversion factors are determined by various standards making bodies. The problem remaining is the method of computation. The purpose of this paper is to compare two methods for computing these factors: analytic and Monte Carlo.

Multisphere default spectra--solution spectrum and dosemeter response implications.

Initial calibration of a multisphere spectroscopy system has been completed at Los Alamos National Laboratory using four standard calibration scenarios. Spectrum unfolding was performed using three methods of constructing the default spectrum: simple parameter models, Monte Carlo calculations and physical measurement. Comparisons of the resulting spectra for each solution method are presented. Implications of the spectral solutions upon dosemeter characterisation are addressed.

Using operational equipment to read accident dosemeters.

Analysis of accident dosemeters usually involves the use of laboratory-based counting equipment. Gamma spectrometers are used for indium, copper and gold, and alpha-beta detectors for sulphur. This equipment is usually not easily transported due to the shielding required and the weight and delicacy of the counters. For intercomparison studies that require reading the dosemeters on site, a transportable system is required unless the site operating the study can count samples for all the participants. In the case of an actual accident these systems would have a difficulty in counting a large number of accident dosemeters. In an accident, personnel are usually subdivided according to their level of exposure. Those exposed to higher doses are treated immediately. An alternate system should be made available to handle the dosemeters worn by those personnel are likely to receive lower doses. Improvements in portable operational equipment for gamma and beta monitoring allow their use as spectrometers. Such a system was used for the SILENE intercomparison conducted at IRSN Valduc on 12 June and 19, 2002, and the preliminary results compared well with the other participants.

Laser illuminated etched track scattering (LITES) dosimetry system.

Los Alamos National Labs (LANL) has developed an etched track foil (CR-39) reader for neutron dose between 0 and 50.0 mSv. Currently, the US Department of Energy mandates general employee annual exposure not to exceed 50.0 mSv (5 rem). At LANL, due to a non-linear response at higher exposures. accepted practice only uses an Autoscan 60 system up to 3 mSv. The LITES system, however, has demonstrated linear response to 50 mSv, where the proprietary design measures the amount of laser light scattered by the etched tracks, proportional to dose. A collection of calibrated foils was counted by an Autoscan 60 and the LITES prototype, and the Autoscan 60 showed good linearity when counting exposure up to about 15 mSv, but not for higher exposures. From 0 to 50 mSv, the Autoscan 60 had a correlation coefficient of R2 = 0.941 and the LITES system had R2 = 0.991.

Audiotapes of oncology consultations: only for the first consultation?

BACKGROUND: Patients value audiotapes of their oncology consultations and letters summarising the discussion, and report improved recall and satisfaction when they receive them. However, studies to date have provided these interventions only after the initial or 'bad news' consultation. This study aimed to evaluate the utility of audiotaping routine follow-up oncology consultations. PATIENTS AND METHODS: This was a prospective study following a cohort of consecutive patients attending routine follow-up at oncology outpatient appointments with one oncologist. Patients were approached when they attended their appointment and offered the opportunity to be audiotaped. Acceptance rates and reasons for refusal were documented. Two weeks after the consultation, patients were telephoned regarding their response to the tape and were sent a letter summarising the consultation. Two weeks later they received a further telephone call regarding the letter and their perceptions of the comparative value of the two interventions. RESULTS: Seventy-five per cent of patients were female and for 40% English was not their first language. The patients had attended a median of 14 previous oncology appointments; 52 patients were offered audiotaping, 43 accepted and 30 decided to take home a copy of the audiotape. One patient felt recording had limited the discussion. Patients refused the tape most commonly because they felt no need for this aid, and accepted it most commonly to aid recall or share with family. Twenty-six patients listened to the tape, 14 did so more than once. Twenty had shared it with another person and over 75% thought it was useful. The majority (57%) preferred to receive both the tape and letter, with three preferring the tape alone and seven the letter. Married patients and those receiving bad news were more likely to want the tape. CONCLUSIONS: Audiotaping follow-up consultations is an inexpensive procedure that is appreciated by the majority of patients. Randomised controlled trials of their impact are warranted.

A comparison of endoscopic ultrasound, magnetic resonance imaging, and exam under anesthesia for evaluation of Crohn's perianal fistulas.

BACKGROUND & AIMS: To determine accuracy of endoscopic ultrasound (EUS) and magnetic resonance imaging (MRI) for evaluation of Crohn's disease perianal fistulas. METHODS: Thirty-four patients with suspected Crohn's disease perianal fistulas were prospectively enrolled in a blinded study comparing EUS, MRI, and examination under anesthesia (EUA). Fistulas were classified according to Parks' criteria, and a consensus gold standard was determined for each patient. Acceptable accuracy was defined as agreement with the consensus gold standard for > or =85% of patients. RESULTS: Three patients did not undergo MRI; 1 did not undergo EUS or EUA; and consensus could not be reached for 1. Thirty-two patients had 39 fistulas (20 trans-sphincteric, 5 extra-sphincteric, 6 recto-vaginal, 8 others) and 13 abscesses. The accuracy of all 3 modalities was > or =85%: EUS 29 of 32 (91%, confidence interval [CI] 75%-98%), MRI 26 of 30 (87%, CI 69%-96%), and EUA 29 of 32 (91%, CI 75%-98%). Accuracy was 100% when any 2 tests were combined. CONCLUSIONS: EUS, MRI, and EUA are accurate tests for determining fistula anatomy in patients with perianal Crohn's disease. The optimal approach may be combining any 2 of the 3 methods.

Bleeding from cavernous angiomatosis of the rectum in Klippel-Trenaunay syndrome: report of three cases and literature review.

Klippel-Trenaunay syndrome (KTS) is a congenital vascular anomaly characterized by limb hypertrophy, cutaneous hemangiomas, and varicosities. GI hemorrhage is a potentially serious complication secondary to diffuse hemangiomatous involvement of the gut. We report on three patients with KTS who presented with transfusion-dependent anemia and life-threatening bleeding due to extensive cavernous hemangiomas involving the rectum. Two patients were treated by proctocolectomy and coloanal anastomosis, which preserved anal function while controlling bleeding. The third patient required an abdominoperineal resection because of extensive rectal, perianal, and perineal angiomatosis. The literature on the evaluation and management of GI hemorrhage in KTS, particularly of colorectal origin, is reviewed.

Intraoperative irradiation for locally recurrent colorectal cancer in previously irradiated patients.

PURPOSE: Information in the literature regarding salvage treatment for patients with locally recurrent colorectal cancer who have previously been treated with high or moderate dose external beam irradiation (EBRT) is scarce. A retrospective review was therefore performed in our institution to determine disease control, survival, and tolerance in patients treated aggressively with surgical resection and intraoperative electron irradiation (IOERT) +/- additional EBRT and chemotherapy. METHODS AND MATERIALS: From 1981 through 1994, 51 previously irradiated patients with recurrent locally advanced colorectal cancer without evidence of distant metastatic disease were treated at Mayo Clinic Rochester with surgical resection and IOERT +/- additional EBRT. An attempt was made to achieve a gross total resection before IOERT if it could be safely accomplished. The median IOERT dose was 20 Gy (range, 10--30 Gy). Thirty-seven patients received additional EBRT either pre- or postoperatively with doses ranging from 5 to 50.4 Gy (median 25.2 Gy). Twenty patients received 5-fluorouracil +/- leucovorin during EBRT. Three patients received additional cycles of 5-fluorouracil +/- leucovorin as maintenance chemotherapy. RESULTS: Thirty males and 21 females with a median age of 55 years (range 31--73 years) were treated. Thirty-four patients have died; the median follow-up in surviving patients is 21 months. The median, 2-yr, and 5-yr actuarial overall survivals are 23 months, 48% and 12%, respectively. The 2-yr actuarial central control (within IOERT field) is 72%. Local control at 2 years has been maintained in 60% of patients. There is a trend toward improved local control in patients who received > or =30 Gy EBRT in addition to IOERT as compared to those who received no EBRT or <30 Gy with 2-yr local control rates of 81% vs. 54%. Distant metastatic disease has developed in 25 patients, and the actuarial rate of distant progression at 2 and 4 years is 56% and 76%, respectively. Peripheral neuropathy was the main IOERT-related toxicity; 16 (32%) patients developed neuropathies (7 mild, 5 moderate, 4 severe). Ureteral narrowing or obstruction occurred in seven patients. All but one patient with neuropathy or ureter fibrosis received IOERT doses > or =20 Gy. CONCLUSION: Long-term local control can be obtained in a substantial proportion of patients with aggressive combined modality therapy, but long-term survival is poor due to the high rate of distant metastasis. Re-irradiation with EBRT in addition to IOERT appears to improve local control. Strategies to improve survival in these poor-risk patients may include the more routine use of conventional systemic chemotherapy or the addition of novel systemic therapies.