Hematocrit Measurement with R2* and Quantitative Susceptibility Mapping in Postmortem Brain.

BACKGROUND AND PURPOSE: Noninvasive venous oxygenation quantification with MR imaging will improve the neurophysiologic investigation and the understanding of the pathophysiology in neurologic diseases. Available MR imaging methods are limited by sensitivity to flow and often require assumptions of the hematocrit level. In situ postmortem imaging enables evaluation of methods in a fully deoxygenated environment without flow artifacts, allowing direct calculation of hematocrit. This study compares 2 venous oxygenation quantification methods in in situ postmortem subjects. MATERIALS AND METHODS: Transverse relaxation (R2*) mapping and quantitative susceptibility mapping were performed on a whole-body 4.7T MR imaging system. Intravenous measurements in major draining intracranial veins were compared between the 2 methods in 3 postmortem subjects. The quantitative susceptibility mapping technique was also applied in 10 healthy control subjects and compared with reference venous oxygenation values. RESULTS: In 2 early postmortem subjects, R2* mapping and quantitative susceptibility mapping measurements within intracranial veins had a significant and strong correlation (R2 = 0.805, P = .004 and R2 = 0.836, P = .02). Higher R2* and susceptibility values were consistently demonstrated within gravitationally dependent venous segments during the early postmortem period. Hematocrit ranged from 0.102 to 0.580 in postmortem subjects, with R2* and susceptibility as large as 291 seconds-1 and 1.75 ppm, respectively. CONCLUSIONS: Measurements of R2* and quantitative susceptibility mapping within large intracranial draining veins have a high correlation in early postmortem subjects. This study supports the use of quantitative susceptibility mapping for evaluation of in vivo venous oxygenation and postmortem hematocrit concentrations.

Defining endoscopic response and remission in ulcerative colitis clinical trials: an international consensus.

BACKGROUND: Recently, endpoints for clinical trials have been changing from measuring clinical response to mucosal healing in ulcerative colitis. Endoscopic evaluation is the current gold standard to assess mucosal lesions and has become a major measure of therapeutic efficacy in addition to patients reported outcomes. AIM: To achieve consensus on endoscopic definitions of remission and response for clinical trials in patients with ulcerative colitis. METHODS: In reaching the current international recommendations on an International Organization For the Study of Inflammatory Bowel Disease (IOIBD) initiative, we first performed a systematic review of technical aspects of endoscopic scoring systems. Then, to achieve consensus on endoscopic definitions of remission and response for clinical trials, we conducted a two-round vote using a Delphi-style process among fifteen specialists in the field of inflammatory bowel diseases. RESULTS: The literature review showed that many endoscopic indices have been proposed to evaluate disease activity in ulcerative colitis; most are unvalidated and arbitrary definitions have been used in clinical trials for defining endoscopic response or remission. At the end of the voting process, the investigators ranked initially the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) 0 for the definition of endoscopic remission, and a decrease in Mayo endoscopic score ≥1 grade or a decrease in UCEIS ≥2 points for the definition of endoscopic response in ulcerative colitis. CONCLUSIONS: These international recommendations represent the first consensus on measurement indices for endoscopic outcomes in ulcerative colitis. They should be subject to prospective testing in clinical trials of ulcerative colitis.

Diamond-like-carbon nanoparticle production and agglomeration following UV multi-photon excitation of static naphthalene/helium gas mixtures.

We report the formation of nanoparticles with significant diamond character after UV multi-photon laser excitation of gaseous naphthalene, buffered in static helium gas, at room temperature. The nanoparticles are identified in situ by their absorption and scattering spectra between 400 and 850 nm, which are modeled using Mie theory. Comparisons of the particles' spectroscopic and optical properties with those of carbonaceous materials indicate a sp(3)/sp(2) hybridization ratio of 8:1 of the particles formed. The particle extinction in the closed static (unstirred) gas-phase system exhibits a complex and quasi-oscillatory time dependence for the duration of up to several hours with periods ranging from seconds to many minutes. The extinction dynamics of the system is based on a combination of transport features and particle interaction, predominantly agglomeration. The relatively long period of agglomeration allows for a unique analysis of the agglomeration process of diamond-like carbon nanoparticles in situ.

Review article: acute severe ulcerative colitis - evidence-based consensus statements.

BACKGROUND: Acute severe ulcerative colitis (ASUC) is a potentially life-threatening complication of ulcerative colitis. AIM: To develop consensus statements based on a systematic review of the literature of the management of ASUC to improve patient outcome. METHODS: Following a literature review, the Delphi method was used to develop the consensus statements. A steering committee, based in Australia, generated the statements of interest. Three rounds of anonymous voting were carried out to achieve the final results. Acceptance of statements was pre-determined by ≥80% votes in 'complete agreement' or 'agreement with minor reservation'. RESULTS: Key recommendations include that patients with ASUC should be: hospitalised, undergo unprepared flexible sigmoidoscopy to assess severity and to exclude cytomegalovirus colitis, and be provided with venous thromboembolism prophylaxis and intravenous hydrocortisone 100 mg three or four times daily with close monitoring by a multidisciplinary team. Rescue therapy such as infliximab or ciclosporin should be started if insufficient response by day 3, and colectomy considered if no response to 7 days of rescue therapy or earlier if deterioration. With such an approach, it is expected that colectomy rate during admission will be below 30% and mortality less than 1% in specialist centres. CONCLUSION: These evidenced-based consensus statements on acute severe ulcerative colitis, developed by a multidisciplinary group, provide up-to-date best practice recommendations that improve and harmonise management as well as provide auditable quality assessments.

Compassionate access anti-tumour necrosis factor-α therapy for ulcerative colitis in Australia: the benefits to patients.

BACKGROUND: The efficacy of infliximab has been demonstrated in patients with both acute severe and moderate-severe ulcerative colitis (UC). However, there is a need for 'real-life data' to ensure that conclusions from trial settings are applicable in usual care. We therefore examined the national experience of anti-tumour necrosis factor-α (TNF-α) therapy in UC. METHODS: Case notes review of patients with UC who had received compassionate access (CA) anti-TNF-α therapy from prospectively maintained inflammatory bowel disease databases of six Australian adult teaching hospitals. RESULTS: Patients either received drug for acute severe UC (ASUC) failing steroids (n = 29) or for medically refractory UC (MRUC) (n = 35). In ASUC, the treating physicians judged that anti-TNF-α therapy was successful in 20/29 patients (69%); in these cases, anti-TNF-α was able to be discontinued (after 1-3 infusions in 19/20 responders) as clinical remission was achieved. Consistent with this perceived benefit, only 7/29 (24%) subsequently underwent colectomy during a median follow up of 12 months (interquartile range (IQR) 5-16). Eight of the 35 patients with MRUC (23%) required colectomy during a median follow up of 28 months (IQR 11-43). The majority of these patients (20/35 or 57%) had anti-TNF-α therapy for ≥4 months, whereas, 27/29 (93%) of ASUC patients had CA for ≤3 months. CONCLUSIONS: These data show an excellent overall benefit for anti-TNF-α therapy in both ASUC and MRUC. In particular, only short-duration anti-TNF-α was required in ASUC. These real-life data thus support the clinical trial data and should lead to broader use of this therapy in UC.

Dose tailoring of anti-tumour necrosis factor-alpha therapy delivers useful clinical efficacy in Crohn disease patients experiencing loss of response.

BACKGROUND: 'Dose tailoring' of anti-tumour necrosis factor alpha (TNF-α) therapy in Crohn disease (CD), by dose escalation, or shortening of dosing intervals, has been suggested to regain clinical response following a flare in a proportion of patients. However, reported outcome data are sparse and none exists from Australia. METHOD: In an observational multicentre, retrospective study, the impact of anti-TNF-α dose tailoring on corticosteroid use, the need for surgery and physician perception of clinical efficacy was examined in a real-world setting at six Australian adult teaching hospitals. Demographics, disease characteristics, medications, indication for and duration of dose tailoring were documented. RESULTS: Fifty-five CD patients were identified as requiring dose tailoring and secondary loss of response was the indication in 96%. Either adalimumab (64%) or infliximab (36%) was dose escalated for a median of 5 months (range 1-47), with a median of 20 months follow up (range 3-65). At 3 months, dose tailoring reduced the mean number of days on high-dose corticosteroids (45 vs 23, P = 0.01). Most (78%) patients remained resection free, and 73% of physicians reported good clinical efficacy of dose tailoring. Of those who de-escalated therapy due to induction of remission, long-term (>12 months) follow up and complete data on steroid use were available in 15/28, with 12/15 (80%) remaining steroid free at 1 year. CONCLUSION: Short-term dose tailoring regains disease response in the majority of patients with CD. Of these, most will remain free of corticosteroids at 1 year after de-escalating therapy.

Comparing disease activity indices in ulcerative colitis.

BACKGROUND: Comparisons between disease activity indices for ulcerative colitis (UC) are few. This study evaluates three indices, to determine the potential impact of inter-observer variation on clinical trial recruitment or outcome as well as their clinical relevance. METHODS: One hundred patients with UC were prospectively evaluated, each by four specialists, followed by videosigmoidoscopy, which was later scored by each specialist. The Simple Clinical Colitis Activity (SCCAI), Mayo Clinic and Seo indices were compared by assigning a disease activity category from published thresholds for remission, mild, moderate and severe activity. Inter-observer variation was evaluated using Kappa statistics and its effect for each patient on recruitment and outcome measures for representative clinical trials calculated. Clinical relevance was assessed by comparing an independently assigned clinical category, taking all information into account as if in clinic, with the disease activity assigned by the indices. RESULTS: Inter-observer agreement for SCCAI (κ=0.75, 95% CI 0.70-0.81), Mayo Clinic (κ=0.72, 95% CI 0.67-0.78) and Seo (κ=0.89, 95% CI 0.83-0.95) indices was good or very good as was the agreement for rectal bleeding (κ=0.77) and stool frequency (κ=0.90). Endoscopy in the Mayo Clinic index had the greatest variation (κ=0.38). Inter-observer variation alone would have excluded up to 1 in 5 patients from recruitment or remission criteria in representative trials. Categorisation by the SCCAI, Mayo Clinic and Seo indices agreed with the independently assigned clinical category in 61%, 67% and 47% of cases respectively. CONCLUSIONS: Trial recruitment and outcome measures are affected by inter-observer variation in UC activity indices, and endoscopic scoring was the component most susceptible to variation.

Multi-photon UV photolysis of gaseous polycyclic aromatic hydrocarbons: extinction spectra and dynamics.

The extinction spectra of static naphthalene and static biphenylene vapor, each buffered with a noble gas at room temperature, were measured as a function of time in the region between 390 and 850 nm after UV multi-photon laser photolysis at 308 nm. Employing incoherent broadband cavity enhanced absorption spectroscopy (IBBCEAS), the spectra were found to be unstructured with a general lack of isolated features suggesting that the extinction was not solely based on absorption but was in fact dominated by scattering from particles formed in the photolysis of the respective polycyclic aromatic hydrocarbon. Following UV multi-photon photolysis, the extinction dynamics of the static (unstirred) closed gas-phase system exhibits extraordinary quasi-periodic and complex oscillations with periods ranging from seconds to many minutes, persisting for up to several hours. Depending on buffer gas type and pressure, several types of dynamical responses could be generated (classified as types I, II, and III). They were studied as a function of temperature and chamber volume for different experimental conditions and possible explanations for the oscillations are discussed. A conclusive model for the observed phenomena has not been established. However, a number of key hypotheses have made based on the measurements in this publication: (a) Following the multi-photon UV photolysis of naphthalene (or biphenylene), particles are formed on a timescale not observable using IBBCEAS. (b) The observed temporal behavior cannot be described on basis of a chemical reaction scheme alone. (c) The pressure dependence of the system's responses is due to transport phenomena of particles in the chamber. (d) The size distribution and the refractive indices of particles are time dependent and evolve on a timescale of minutes to hours. The rate of particle coagulation, involving coalescent growth and particle agglomeration, affects the observed oscillations. (e) The walls of the chamber act as a sink. The wall conditions (which could not be quantitatively characterized) have a profound influence on the dynamics of the system and on its slow return to an equilibrium state.

Implementing guidelines on the prevention of opportunistic infections in inflammatory bowel disease.

INTRODUCTION: Opportunistic infections are a key safety concern in the management of patients with inflammatory bowel disease (IBD). Despite the existence of international guidelines, many gastroenterologists have not adopted routine screening and vaccination. The aim of this study was to modify clinical behaviour by use of a simple screening tool. METHODS: A screening and vaccination proforma for hepatitis B, varicella, Influenza, Pneumococcus, human papillomavirus, tuberculosis, hepatitis C and HIV was provided to each participating gastroenterologist. Gastroenterologists were surveyed for awareness of vaccine recommendations and current practice prior to and following the introduction of the proforma. Rates of immunity and the proportion of patients receiving the recommended screening and vaccinations were documented. RESULTS: 30 gastroenterologists at 8 different IBD centres took part in the assessment. A total of 919 patients were included (55% female, 65% Crohn's, 33% ulcerative colitis, 2% indeterminate IBD). Introduction of the proforma increased self-reported gastroenterologist screening from 47% to 97% pre- and post-intervention respectively, p<0.001. After the proforma was applied, vaccination against hepatitis B, varicella, Influenza, and Pneumococcus was recommended in 67%, 2.5%, 75% and 69% of the patients respectively. Of these, 42%, 39%, 66% and 49% patients followed the recommendations and were vaccinated. Cervical smears were recommended in 31%, with 62% of these obtaining the recommended cervical smear. CONCLUSIONS: Implementation of a screening and vaccination proforma significantly changed gastroenterologist self-reported behaviour. Patient compliance with these recommendations was not optimal and suggests the need for further patient education, in addition to other forms of support.

Paraplegia secondary to fracture-subluxation of the thoracic spine sustained playing rugby union football.

Fractures of the spinal column during rugby matches of all codes are rare but catastrophic, especially when associated with spinal cord injury. The cervical spine is vulnerable during trauma to the head and neck in contact sports. Spinal injuries reported during rugby matches have almost exclusively involved the cervical region, often with neurological sequelae. This is the first reported case of paraplegia caused by a fracture-dislocation of the thoracic spine resulting from a low velocity rugby union injury.

Computed tomography and ultrasonography do not improve and may delay the diagnosis and treatment of acute appendicitis.

HYPOTHESIS: Computed tomography (CT) and ultrasonography (US) do not improve the overall diagnostic accuracy for acute appendicitis. DESIGN: Retrospective review. SETTING: University tertiary care center. PATIENTS: Seven hundred sixty-six consecutive patients undergoing appendectomy for suspected appendicitis from January 1, 1995, to December 31, 1999. MAIN OUTCOME MEASURES: Epidemiology of acute appendicitis and the roles of clinical assessment, CT, US, and laparoscopy. RESULTS: The negative appendectomy rate was 15.7%, and the incidence of perforated appendicitis was 14.6%. A history of migratory pain had the highest positive predictive value (91%), followed by leukocytosis greater than 12 x 10(9)/L (90.1%), CT (83.8%), and US (81.3%). The false-negative rates were 60% for CT and 76.1% for US. Emergency department evaluation took a mean +/- SD of 5.2 +/- 5.4 hours and was prolonged by US or CT (6.4 +/- 7.4 h and 7.8 +/- 10.8 h, respectively). The duration of emergency department evaluation did not affect the perforation rate, but patients with postoperative complications had longer evaluations (mean +/- SD, 8.0 +/- 12.7 h) than did those without (4.8 +/- 3.3 h) (P =.04). Morbidity was 9.1%, 6.4% for nonperforated cases and 19.8% for perforated cases. Seventy-six patients had laparoscopic appendectomy, with a negative appendectomy rate of 42.1%, compared with 15.4% for open appendectomy (P<.001). Laparoscopy, however, had minimal morbidity (1.3%) and correctly identified the abnormality in 91.6% of patients who had a normal-appearing appendix. CONCLUSIONS: Migratory pain, physical examination, and initial leukocytosis remain reliable and accurate in diagnosing acute appendicitis. Neither CT nor US improves the diagnostic accuracy or the negative appendectomy rate; in fact, they may delay surgical consultation and appendectomy. In atypical cases, one should consider the selective use of diagnostic laparoscopy instead.

Family history, ethnicity, and relative risk of breast cancer in a prospective cohort study of older women.

In a cohort of 27,578 postmenopausal Iowa women, we examined whether the risk with a family history of breast cancer differs by self-reported ethnicity. A total of 1042 breast cancer cases occurred over 10 years of follow-up. Using a phylogenetic tree, ethnicities were combined into five groups: Scandinavian; English, Scottish, Welsh, and Dutch (ESWD); Irish; German; and Other European. The incidence of breast cancer did not differ significantly by ethnicity, although the highest rates were observed among Scandinavian women (488 per 100,000 per year) and the lowest among Irish women (353 per 100,000 per year). The prevalence of a family history of breast cancer was not significantly associated with ethnicity when only first-degree relatives were considered (P = 0.17), but inclusion of data on second-degree relatives increased the statistical significance of the association (P = 0.003). Differences in mean levels of breast cancer risk factors between ethnicities were generally small but statistically significant. Proportional hazards regression was performed to evaluate potential interactions of family history with ethnicity on breast cancer incidence. A family history of breast cancer was associated with increased relative risks among ESWD, Germans, and Other Europeans but not among Irish and Scandinavians. Relative risk estimates were not attenuated upon addition of known breast cancer risk factors to the model, implying that the distribution of these risk factors by ethnicity is unlikely to explain some of the observed ethnic-specific differences between family history and risk of breast cancer. Results of this study could have implications for studies of common genetic polymorphisms and cancer risk.

Design and application of a low-temperature Peltier-cooling microscope stage.

A light microscopy system has been designed for freezing and lyophilization studies of protein pharmaceuticals. The system consists of a cascade of four Peltier thermoelectric modules in the lyophilization cell to freeze samples to -60 degrees C, controllers to regulate temperature and pressure conditions, and a video camera to record the events under study. Specific demonstration of the system was conducted using recombinant CD4-IgG and human growth hormone (hGH) as model proteins. Observations of recrystallization during warming of frozen CD4-IgG solution and lyophilization of hGH solution are discussed. These examples demonstrate that the system is a useful tool for the fundamental understanding of freezing and lyophilization of protein pharmaceuticals.

Reduced placental villous tree elaboration in small-for-gestational-age pregnancies: relationship with umbilical artery Doppler waveforms.

OBJECTIVE: Our purpose was to investigate the three-dimensional architecture of placental villi from normal and growth-restricted fetuses and relate findings to umbilical artery blood flow velocity waveforms. STUDY DESIGN: Placentas from term (n = 15) and preterm (n = 5) appropriately grown and term (n = 9) and preterm (n = 7) growth-restricted fetuses (birth weight < 10th percentile) were examined to determine the number of arteries per stem villus and the three-dimensional configuration of the villous trees and their vessels. Umbilical blood flow before delivery was assessed by Doppler ultrasonography. The effects of age and growth restriction were determined by two-way analyses of variance. RESULTS: Growth restriction was associated with reduced large vessel wall thickness (p < or = 0.05) but no reduction in the number of these vessels per stem villus. The volumes and surface areas of intermediate and terminal villi were reduced (p < or = 0.001), especially in preterm growth-restricted cases, where a marked reduction in diastolic blood flow velocity was observed in the umbilical artery. CONCLUSIONS: Reduced villous development may contribute to abnormal umbilical artery blood flood flow, as assessed by Doppler ultrasonography, in some cases of intrauterine growth restriction.