Late-Life Body Mass Index, Rapid Weight Loss, Apolipoprotein E ε4 and the Risk of Cognitive Decline and Incident Dementia.

OBJECTIVES: To examine the effect of late-life body mass index (BMI) and rapid weight loss on incident mild cognitive impairment (MCI) and Alzheimer's disease (AD). DESIGN: Prospective longitudinal cohort study. SETTING: National Alzheimer's Coordinating Center (NACC) Uniform Data Set, including 34 past and current National Institute on Aging-funded AD Centers across the United States. PARTICIPANTS: 6940 older adults (n=5061 normal cognition [NC]; n=1879 MCI). MEASUREMENTS: BMI (kg/m2) and modified Framingham Stroke Risk Profile (FSRP) score (sex, age, systolic blood pressure, anti-hypertension medication, diabetes mellitus, cigarette smoking, prevalent cardiovascular disease, atrial fibrillation) were assessed at baseline. Cognition and weight were assessed annually. RESULTS: Multivariable binary logistic regression, adjusting for age, sex, race, education, length of follow-up, and modified FSRP related late-life BMI to risk of diagnostic conversion from NC to MCI or AD and from MCI to AD. Secondary analyses related late-life BMI to diagnostic conversion in the presence of rapid weight loss (>5% decrease in 12 months) and apolipoprotein E (APOE) ε4. During a mean 3.8-year follow-up period, 12% of NC participants converted to MCI or AD and 49% of MCI participants converted to AD. Higher baseline BMI was associated with a reduced probability of diagnostic conversion, such that for each one-unit increase in baseline BMI there was a reduction in diagnostic conversion for both NC (OR=0.977, 95%CI 0.958-0.996, p=0.015) and MCI participants (OR=0.962, 95%CI 0.942-0.983, p<0.001). The protective effect of higher baseline BMI did not persist in the setting of rapid weight loss but did persist when adjusting for APOE ε4. CONCLUSIONS: Higher late-life BMI is associated with a lower risk of incident MCI and AD but is not protective in the presence of rapid weight loss.

PROviding Better ACcess To ORgans: A comprehensive overview of organ-access initiatives from the ASTS PROACTOR Task Force.

The American Society of Transplant Surgeons (ASTS) PROviding better Access To Organs (PROACTOR) Task Force was created to inform ongoing ASTS organ access efforts. Task force members were charged with comprehensively cataloguing current organ access activities and organizing them according to stakeholder type. This white paper summarizes the task force findings and makes recommendations for future ASTS organ access initiatives.

Quality assurance evaluation of spot scanning beam proton therapy with an anthropomorphic prostate phantom.

OBJECTIVE: The purpose of this study was to evaluate spot scanning proton therapy with an anthropomorphic prostate phantom at the Proton Therapy Center of The University of Texas MD Anderson Cancer Center at Houston, TX (PTCH). METHODS: An anthropomorphic prostate phantom from the Radiological Physics Center (RPC), The University of Texas MD Anderson Cancer Center, Houston, TX, was used, which contained thermoluminescent dosemeters and GAFCHROMIC(®) EBT2 film (ISP Technologies, Wayne, NJ). The phantom was irradiated by the Hitachi synchrotron (Hitachi America, Ltd, Tarrytown, NY), and the results were compared between the treatment planning system (TPS) and RPC measurements. RESULTS: RPC results show that the right/left, inferior/superior and posterior/anterior aspects of the coronal/sagittal and EBT2 film measurements were within ±7%/±4 mm of the TPS. The RPC thermoluminescent dosemeter measurements of the prostate and femoral heads were within 3% of the TPS. CONCLUSION: The RPC prostate phantom is a useful mechanism to evaluate spot scanning beam proton therapy within certain confidence levels. ADVANCES IN KNOWLEDGE: The RPC anthropomorphic prostate phantom could be used to establish quality assurance of spot scanning proton beam for patients with prostate cancer.

Cardiac damage induced by immunization with heat-killed Trypanosoma cruzi is not antibody mediated.

Cardiac inflammation that develops during infection with Trypanosoma cruzi may result in part from autoimmunity, which may occur after bystander activation, after parasite-induced cardiomyocyte damage, or molecular mimicry. A/J mice infected with T. cruzi or immunized with heat-killed T. cruzi (HKTC) develop strong autoimmunity accompanied by cardiac damage. To determine whether this cardiac damage occurs via an antibody-dependent mechanism, we analysed T. cruzi-infected and HKTC-immunized mice for the presence of autoantibodies, cardiac antibody deposition, and serum cardiac troponin I as a measure of cardiac damage. We also performed a serum transfer experiment in which sera from T. cruzi-infected and T. cruzi-immunized mice (and controls) were transferred into naïve recipients, which were then analysed for the presence of antibodies and serum troponin. Unlike T. cruzi-infected mice, T. cruzi-immunized mice did not show significant antibody deposition in the myocardium. These results indicate that antibody deposition does not precede cardiac damage and inflammation in mice immunized with or infected with T. cruzi. Serum adoptive transfer did not induce cardiac damage in any recipients. Based on these findings, we conclude that the cardiac damage induced by immunization with HKTC is not mediated by antibodies.

SU-E-T-103: Three-Dimensional Measurements of Dose and LET from a Proton Beam via Polymer Gel Dosimetry.

PURPOSE: To obtain and assess the accuracy of 3D dose distributions and LET maps from a passively-scattered proton beam through the use of LET-dependent and LET-independent polymer gel formulations. METHODS: Dose measurements were performed with BANG3-Pro2 (MGS Research, Inc, Madison, CT) polymer gel dosimeters. The dosimeters were mixed from kits and were poured into 14.5 cm high by 15 cm diameter acrylic cylinders. For LET measurements, a new BANG3-Pro variant intended for use as an 'LET- meter' was employed. Initial irradiations were performed using a 200 MeV passively scattered proton beam with a 4 cm spread out Bragg peak (SOBP), delivering a physical dose of 3 Gy to the center of the SOBP. Dosimeters were read out using the OCTOPUS-IQ (MGS Research, Inc, Madison, CT) optical CT scanner. The optical densities measured in the gel were compared against ion chamber data to assess the accuracy of the dosimeter. RESULTS: Initial analysis indicates 80% of points measured along the central axis agreed with ion chamber data at the ±5%/±3mm level in the sensitive region of the gel. An artifact in the reconstructed image produced inaccurate readings beyond the depth of 50% dose on the distal edge of the SOBP, resulting in the majority of the agreement failures. CONCLUSIONS: BANG3-Pro2 polymer gel dosimeters demonstrate promise as a 3D dosimeter for use in proton therapy. The dosimetric data obtained to date will be used as the baseline measurement against which the LET-sensitive BANG3-Pro formulation will be compared for the measurement of proton LET.

SU-E-T-215: A Technique for Treating Patients outside the Mosaiq R&V System for TrueBeam Users (or 4DTC).

PURPOSE: When the record and verify (R&V) system (Mosaiq, Elekta Medical Systems) is unavailable to send information to the treatment console of the linear accelerator (Varian Clinac, Varian Medical Systems), treatment is manually delivered by entering parameters into the treatment console and loading backed up MLC files. The new linear accelerator, the TrueBeam (Varian Medical Systems) lacks the ability to manually deliver treatment by entering machine parameters into the treatment console. METHODS: The TrueBeam can only deliver treatments using the R&V system or loading DICOM RT plan files directly in File Mode. Every time a prescription site is sent from the R&V system to the accelerator, a DICOM RT plan file is created by the R&V system. A script was created that reads the headers of these files, copies them to the treatment console and renames them in an identifiable form. At the end of each treatment day, the script is executed transferring only the DICOM RT plan files created that treatment day. A contingency report is then generated from the R&V system, which contains machine parameters for all fields for all patients under treatment. When the R&V system is unavailable the RT plan files are opened in file mode, and the machine parameters are verified using the contingency report before delivery. This system was tested on a cohort of patients. Each patient's plan was opened in file mode and the machine parameters were verified against the patient's planned treatment in the R&V system. RESULTS: All files opened in file mode were identical to the information stored in the R&V system. This was tested both on the TrueBeam and accelerators having the 4DTC. CONCLUSIONS: Our technique was validated and is an alternative method for delivering treatment when the R&V system is unavailable.

SU-E-T-186: An Automated Quality Assurance Tool for HDR Treatment Planning.

PURPOSE: Treatment planning for high dose rate (HDR) brachytherapy requires many user inputs, all of which are potential sources of error. The goal of quality assurance (QA) is to ensure that errors are not made. In this study, we developed a software program to analyze the treatment printout from the HDR treatment planning computer and flag any suspected errors. METHODS: The treatment printout from the HDR planning computer is imported by the software. The software then performs the following checks: (1) verifies that the correct source was chosen (we have multiple in our database), (2) performs an independent decay of the Ir-192 source, (3) verifies source step size, (4) verifies the offsets and indexer lengths in the catheter definitions based upon expected values for the applicator used, (4) performs an independent 2nd check of dose to a cloud of dose points surrounding the treatment region, (5) verifies that the dose per fraction and the number of fractions were entered correctly in the planning computer, and (6) verifies that the dose volume histogram (DVH) metrics were within acceptable tolerances. The software then prints this information to a PDF file, which is appended to the original treatment printout and placed in the patient's medical record. RESULTS: This QA tool has now been implemented for six months in our clinic, and is a critical QA tool in our HDR program. Although each plan is checked by an independent 2nd physicist, this tool provides an additional independent check on the treatment plan. CONCLUSIONS: A simple series of automatic 2nd checks helps reduce the risk of errors occurring in the treatment planning portion of HDR brachytherapy and can easily be implemented.

Transplant surgery fellow perceptions about training and the ensuing job market-are the right number of surgeons being trained?

The American Society of Transplant Surgeons (ASTS) sought whether the right number of abdominal organ transplant surgeons are being trained in the United States. Data regarding fellowship training and the ensuing job market were obtained by surveying program directors and fellowship graduates from 2003 to 2005. Sixty-four ASTS-approved programs were surveyed, representing 139 fellowship positions in kidney, pancreas and/or liver transplantation. One-quarter of programs did not fill their positions. Forty-five fellows graduated annually. Most were male (86%), aged 31-35 years (57%), married (75%) and parents (62%). Upon graduation, 12% did not find transplant jobs (including 8% of Americans/Canadians), 14% did not get jobs for transplanting their preferred organ(s), 11% wished they focused more on transplantation and 27% changed jobs early. Half fellows were international medical graduates; 45% found US/Canadian transplant jobs, particularly 73% with US/Canadian residency training. Fellows reported adequate exposure to training volume, candidate selection, pre/postoperative care and organ procurement, but not to donor management/selection, outpatient care and core didactics. One-sixth noted insufficient 'mentoring/preparation for a transplantation career'. Currently, there seem to be enough trainees to fill entry-level positions. One-third program directors believe that there are too many trainees, given the current and foreseeable job market. ASTS is assessing the total workforce of transplant surgeons and evolving manpower needs.

Weight-reducing diets: are there any differences?

This paper compares the efficacy of two widely used weight-loss diets differing in macronutrient composition - a low-carbohydrate diet versus a low-fat diet. Although "a calorie is a calorie" under the controlled conditions of a metabolic unit (i.e., only the level of calorie intake matters and not the source of calories), we conclude that these interrelationships are far more complex in the free-living situation. The different diet-related factors that condition energy balance, including total energy intake, satiety and hunger sensory triggers, and palatability, must be considered when assessing the efficacy of weight-reducing diets of different macronutrient composition.

Dietary fats, eating guides, and public policy: history, critique, and recommendations.

Controversies over the nutrition science of dietary fat, and equally over the advice furnished to consumers about dietary fat, have confounded US nutrition policies and eating guidance for the last 90 years. This is so despite the remarkable congruence between the first US food guides (1916) and the most recent (2000 Dietary Guidelines for Americans), both of which state that dietary fats should be consumed "moderately." The 2002 Report of the US Food and Nutrition Board (issued jointly by the United States and Canada) quantifies this by stating that healthy dietary fat should constitute "25-35 percent of calories." However, the US consumer guide, the Food Guide Pyramid (released in 1992 but based on data from the early 1980s) states that dietary fats should be consumed "sparingly," which is explained to be "a diet low in fat." This direct conflict in official dietary policies causes consumer confusion and erodes efforts of public and private health promotion efforts to stem the increasing incidence of overweight and obesity in Americans. The most successful population-wide dietary behavior modification program in US history was the food rationing program in World War II. Its successes were based equally on consensus nutrition profiles for good health and messages that communicated the rationing program effectively. The current US incidence of overweight and obesity, and the chronic diseases to which they are precursors, will be mitigated and prevented only with major changes in national dietary policies and programs based on successful experiences and models. The first step in this much-needed process is acknowledgment that current dietary guidance and education policies have been and are unsatisfactory.

Links between early adrenal function and respiratory outcome in preterm infants: airway inflammation and patent ductus arteriosus.

OBJECTIVE: To investigate the relationship of cortisol concentrations during the first week of life to patent ductus arteriosus (PDA), markers of lung inflammation, and respiratory outcome in very low birth weight infants. METHODS: Newborns <1,500 g birth weight were prospectively enrolled at 2 centers. Serum cortisol was measured 3 times during days 2 to 7 of life. Tracheal lavage was performed on intubated infants and analyzed for interleukin-1beta, -6, and -8, and for total protein, albumin, and alpha-1 protease inhibitor. Infants receiving prenatal glucocorticoids were excluded. RESULTS: We obtained 337 cortisol values from 125 infants. Infants treated for PDA had lower cortisol values after day 2. One hundred thirty-three tracheal fluid samples were obtained on matching days from 71 intubated infants. Cortisol correlated inversely with tracheal interleukins and proteins. Lower cortisol values during the second half of the week correlated with longer duration of supplemental oxygen therapy and with subsequent development of chronic lung disease at 28 days and at 36 weeks. CONCLUSION: Infants with lower cortisol values in the first week of life had an increased incidence of PDA, increased lung inflammation, and an increased incidence of chronic lung disease. These findings suggest that early adrenal insufficiency may underlie the previously observed association of increased lung inflammation and PDA with adverse respiratory outcome in this population.

Prophylaxis against early adrenal insufficiency to prevent chronic lung disease in premature infants.

UNLABELLED: BACKGROUND. Many extremely low birth weight infants (<1000 g) show biochemical evidence of adrenal insufficiency in the first week of life, correlating with subsequent development of chronic lung disease (CLD). METHODS: We conducted a randomized, double-masked, placebo-controlled pilot study to test whether early treatment with low-dose hydrocortisone for 12 days (1 mg/kg/day for 9 days followed by.5 mg/kg/day for 3 days), begun before 48 hours of life, would increase the likelihood of survival without CLD. RESULTS: Forty patients were enrolled at two centers. Birth weight and gestation were similar for treatment and placebo groups: 732 +/- 135 g versus 770 +/- 135 g and 25.2 +/- 1.3 weeks versus 25.4 +/- 1.5 weeks. More infants treated with hydrocortisone achieved study success, defined as survival without supplemental oxygen at 36 weeks' postconception (12/20 [60%] vs 7/20 [35%]). Lower birth weight, histologic chorioamnionitis, and preeclampsia were significant risk factors, whereas study center, prenatal steroids, sex, and ethnicity were not significant. Hydrocortisone treatment decreased days on >40% oxygen, days on >25% oxygen, days on ventilator, and oxygen at discharge. Among infants exposed to chorioamnionitis, hydrocortisone treatment also was associated with increased enteral intake during the first month of life and with increased weight at 36 weeks' postconception. Five treated infants and 6 placebo infants developed sepsis; 3 in each group died. CONCLUSIONS: First, early treatment with low-dose hydrocortisone in this population of extremely low birth weight infants increased the likelihood of survival without CLD. Second, the benefit was particularly apparent in infants with chorioamnionitis. Third, a larger multicenter trial is needed to verify the primary outcome and to better evaluate risks and benefits.

Positive relationship of cortisol concentrations and oral nutrition to epidermal growth factor concentrations in preterm infants.

We have suggested from previous studies that increases in early neonatal epidermal growth factor (EGF) concentrations were dependent on adequate glucocorticoid hormone concentrations. In order to examine this relationship, matched values for cortisol and EGF in 193 preterm infants on days 2 and 6 were compared. Gestational age had a significant positive effect on EGF concentrations for those infants receiving oral nutrition and there was also a positive relationship between nutrition and cortisol concentration. Cortisol was then used as an independent factor and was significantly (p = 0. 01) related to EGF values such that as cortisol concentrations increased, EGF values also increased. In summary, we suggest that these results are consistent with a role for cortisol in the control of the EGF pattern in the newborn period.

The effect of calcium supplements on rectal mucosal proliferation.

Seventy-nine patients with colorectal adenomata were randomised to receive calcium carbonate (3,000 mg) or placebo in a double-blind randomised trial to assess the short- and long-term effects on rectal mucosal proliferation measured by the in vitro metaphase arrest technique crypt cell production rate (CCPR). There was no significant difference in mean CCPR between the groups before treatment or after 3 or 12 months. In those patients randomised to calcium, CCPR fell at both 3 months [9.0 (2.8) cc c-1 h-1, t = 3.15, d.f = 76, P = 0.002] and 12 months [9.2 (3.3) cc c-1 h-1 t = 2.7, d.f. = 74, P = 0.009] compared with pretreatment CCPR [12.2 (5.5) cc c-1 h-1]. We have demonstrated that calcium had no effect on mucosal proliferation compared with placebo. The results on adenoma formation are awaited.

Optimal cost-effective timing of cranial ultrasound screening in low-birth-weight infants.

Our aim in this study was to determine whether delaying the initial screening cranial ultrasound on infants of low birth weight until the 2nd week of life affects clinical diagnosis and cost of patient care. Data were reviewed on all premature infants of less than 33 weeks gestation or less than 1500 g birth weight admitted to the Neonatal Intensive Care Unit between January 1989 and August 1992. Babies admitted before August 1991 were screened on day 4 or 5 with a second scan frequently performed on day 14; babies admitted after that date were screened once between days 10-14. Populations were compared for (1) proportion of ultrasound findings considered normal on final diagnosis; (2) incidence of major and minor abnormalities; (3) periventricular leukomalacia (PVL); (4) change in diagnosis from 1st to 2nd week; and (5) number of studies performed per patient. The study group was composed of 499 eligible infants. Demographic features of infants screened in the 1st vs. 2nd week of life were similar, with comparable diagnoses of major and minor intracranial hemorrhage and ventricular dilatation; however, more patients screened in the 1st week had questionable PVL diagnosed (p = 0.04). There was a significant decrease in the number of scans per patient in the group screened in the 2nd week (p < 0.004). Routine screening may be delayed until the 2nd week without compromising patient care. Widespread use of a similar screening protocol would result in significantly fewer studies being performed, with an estimated saving, in the USA, of more than $3 million annually.

Wheat fibre, lactulose and rectal mucosal proliferation in individuals with a family history of colorectal cancer.

In a single-blind study 38 individuals at increased risk of developing colorectal cancer because of a family history of the disease were randomized to take 10.5 g wheat fibre (Trifyba) or 60 ml lactulose daily for 12 weeks. Rectal biopsies were taken before and after treatment and rectal mucosal proliferation was measured by the crypt cell production rate (CCPR). The mean(s.d.) CCPR was significantly lower in those taking wheat fibre after 12 weeks (7.2(3.4) crypt cells per crypt per h) compared both with values obtained before treatment with wheat fibre (10.2(5.1) crypt cells per crypt per h; P = 0.02) and after treatment with lactulose (9.4(3.8) crypt cells per crypt per h; P = 0.05). Proliferation in the lactulose group was not significantly different at 12 weeks compared with the value obtained before treatment. This study confirms an antiproliferative effect of wheat fibre in a group of high-risk individuals.

DNA content of rectal mucosa and rectal mucosal proliferation in individuals at high risk of colorectal cancer.

Genetic changes are important in the development of colorectal cancer. Ploidy and rectal mucosal proliferation were measured in histologically normal rectal mucosa of 85 individuals (mean age 59 years, range 29-74) who had a total colonoscopy. Fifty-one subjects had an adenoma or were undergoing adenoma surveillance. Twenty-two subjects had a strong family history of colorectal cancer and 12 individuals comprised a control group who had a normal colonoscopy without a family history of colorectal cancer. An abnormal DNA content (aneuploidy) was found in the normal mucosa of nine (10.6%) individuals. There was no significant difference in rectal mucosal proliferation with those who had aneuploidy and those who had diploidy. There was a trend towards increased proliferation in those with aneuploidy and adenomas, compared with controls. Of the 35 individuals undergoing adenoma surveillance, eight had recurrent adenomas, and three of these expressed aneuploidy. In the other 27, in whom no adenomas were found, no individual expressed aneuploidy (P = 0.01, Fisher's exact test). Aneuploidy within histologically normal mucosa is an unusual feature, which requires further investigation, particularly in patients developing adenomas.

Cell kinetics of the in vitro metaphase arrest technique and the clinical applications.

The in vitro metaphase arrest technique (crypt cell production rate-CPPR) has been used to measure human rectal mucosal proliferation. Study of preincubation times, dose response curves and lag phases suggest that a concentration of vincristine of 5 micrograms/ml and 16 hour preincubation with time point increments between 25 and 125 minutes give optimal conditions for measuring rectal mucosal proliferation. Twenty individuals had rectal CCPR repeated without intervention of any kind. Close correlation was found between the two values (r = 0.89 and P = 0.0001). The effect of polyethylene glycol bowel preparation was also studied in 35 subjects. There was good correlation (r = 0.66, P = 0.007). There was close correlation between rectal and caecal CCPR as measured in 20 patients who had colonoscopy (r = 0.72, P = 0.0003). The in vitro metaphase arrest technique is a useful parameter of rectal mucosal proliferation and may be used with confidence in a number of different clinical situations.

The identification of high and low risk groups for colorectal cancer using rectal mucosal crypt cell production rate (CCPR).

Rectal mucosal proliferation was measured in 116 individuals using the metaphase arrest technique crypt cell production rate (CCPR). CCPR was found to be significantly elevated in individuals with adenomas (n = 42, CCPR = 13 cc c-1h-1, range 7-25 Cl 10-15) compared with normals (n = 21, CCPR = 10 cc c-1h-1 range 5-24 Cl 7-11, Mann-Whitney P = 0.001 z = 3.2). Mucosal proliferation was increased among individuals who were undergoing adenoma follow up but in whom no further adenomas were found (n = 37 CCPR = 12 range 5-26 cc c-1h-1 Cl 10-14) compared to controls (Mann-Whitney P = 0.01 z = 2.4) Proliferation in vegetarians i.e. low risk (n = 16) was similar to controls. Measurement of proliferative indices in rectal mucosa by the stathmokinetic technique CCPR can discriminate between high and low risk groups for colorectal cancer.

Jaundice in the healthy newborn infant: a new approach to an old problem.

We measured the serum bilirubin concentrations in 2,416 consecutive infants admitted to our well baby nursery. The maximal serum bilirubin concentration exceeded 12.9 mg/dL (221 mumol/L) in 147 infants (6.1%), and these infants were compared with 147 randomly selected control infants with maximal serum bilirubin levels less than or equal to 12.9 mg/dL. A serum bilirubin concentration greater than 12.9 mg/dL was associated strongly with breast-feeding (P = .0000) and percentage of weight loss after birth (P = .0001), as well as with maternal diabetes, oriental race, decreased gestational age, male sex, bruising, and induction of labor with oxytocin. Risk ratios and the risk of jaundice were calculated for hypothetical infants in the presence and absence of these variables. These calculations show that, in certain infants, "nonphysiologic" jaundice is likely to develop and its presence in such infants might not require laboratory investigations. In others, a modest degree of hyperbilirubinemia could be cause for concern. An awareness of these factors and their potential contribution to serum bilirubin levels permits a more rational approach to the action levels used for the investigation of jaundice in the newborn. We need a new definition of physiologic jaundice.