Prescribing and Consumption of Opioids After Primary, Unilateral Total Hip and Knee Arthroplasty in Opioid-Naive Patients.

BACKGROUND: This cohort study was designed to determine the discrepancy between the quantity of opioid prescribed vs that which was consumed after total knee arthroplasty (TKA) and total hip arthroplasty (THA) in opioid-naive patients. METHODS: Seven hundred twenty-three opioid-naive patients (426 TKAs and 297 THAs) from 7 hospitals in Michigan were contacted within 3 months of their surgery. Opioid prescribing and self-reported consumption was calculated in oral morphine equivalents (OMEs). Secondary outcomes included opioid refill in the first 90 days, pain in the first 7 days post-operatively, and satisfaction with pain care. RESULTS: For TKA, the mean prescribing was 632 mg OME (±229), and the mean consumption was 416 mg (±279). For THA, the mean prescribing was 584 mg OME (±335), and the mean consumption was 285 mg (±301). There were no associations between the amount of opioid prescribed and the likelihood of refill, post-operative pain, or satisfaction with pain control. The amount of opioid prescribed was associated with increased consumption, such that each increase of 1 pill was associated with approximately an additional half pill consumed after adjusting for other covariates. Moreover, 48.2% felt that they received "More" or "Much more" opioid than they needed. CONCLUSION: We recommend no more than 50 tablets of 5 mg oxycodone or its equivalent after TKA and 30 tablets after THA. Although dose reductions in other surgeries have not resulted in harm, continued assessment is needed to ensure that there are no unintended effects of opioid reduction, including worsened pain, decreased satisfaction, emergency department visits, or hospital readmissions. LEVEL OF EVIDENCE: Level III; Retrospective, cohort study.

PP2A-B55/SUR-6 collaborates with the nuclear lamina for centrosome separation during mitotic entry.

Across most sexually reproducing animals, centrosomes are provided to the oocyte through fertilization and must be positioned properly to establish the zygotic mitotic spindle. How centrosomes are positioned in space and time through the concerted action of key mitotic entry biochemical regulators, including protein phosphatase 2A (PP2A-B55/SUR-6), biophysical regulators, including dynein, and the nuclear lamina is unclear. Here, we uncover a role for PP2A-B55/SUR-6 in regulating centrosome separation. Mechanistically, PP2A-B55/SUR-6 regulates nuclear size before mitotic entry, in turn affecting nuclear envelope-based dynein density and motor capacity. Computational simulations predicted the requirement of PP2A-B55/SUR-6 regulation of nuclear size and nuclear-envelope dynein density for proper centrosome separation. Conversely, compromising nuclear lamina integrity led to centrosome detachment from the nuclear envelope and migration defects. Removal of PP2A-B55/SUR-6 and the nuclear lamina simultaneously further disrupted centrosome separation, leading to unseparated centrosome pairs dissociated from the nuclear envelope. Taking these combined results into consideration, we propose a model in which centrosomes migrate and are positioned through the concerted action of PP2A-B55/SUR-6-regulated nuclear envelope-based dynein pulling forces and centrosome-nuclear envelope tethering. Our results add critical precision to models of centrosome separation relative to the nucleus during spindle formation in cell division.

Verification by the FISH translocation assay of historic doses to Mayak workers from external gamma radiation.

The aim of this study was to apply the fluorescence in situ hybridization (FISH) translocation assay in combination with chromosome painting of peripheral blood lymphocytes for retrospective biological dosimetry of Mayak nuclear power plant workers exposed chronically to external gamma radiation. These data were compared with physical dose estimates based on monitoring with badge dosimeters throughout each person's working life. Chromosome translocation yields for 94 workers of the Mayak production association were measured in three laboratories: Southern Urals Biophysics Institute, Leiden University Medical Center and the former Health Protection Agency of the UK (hereinafter Public Health England). The results of the study demonstrated that the FISH-based translocation assay in workers with prolonged (chronic) occupational gamma-ray exposure was a reliable biological dosimeter even many years after radiation exposure. Cytogenetic estimates of red bone marrow doses from external gamma rays were reasonably consistent with dose measurements based on film badge readings successfully validated in dosimetry system "Doses-2005" by FISH, within the bounds of the associated uncertainties.

Functional outcomes of MPFL reconstruction vs. graft tissue placement.

BACKGROUND: The medial patellofemoral ligament (MPFL) is essential for the maintenance of correct biomechanical function of the knee. Reconstruction of the MPFL is commonly used in the restoration of patellofemoral stability after traumatic lateral subluxation of the patella. Although a method to accurately determine the MPFL's insertion point has been described, it remains unclear if anatomic placement of MPFL graft tissue is essential for preservation of knee function after MPFL reconstruction. Thus, the purpose of this study was to determine the importance of anatomic placement of MPFL graft tissue for the preservation of knee function following MPFL reconstruction operations. METHODS: Twenty-seven subjects who underwent MPFL reconstruction operations were retrospectively analyzed. Postoperative radiographs were reviewed. Measurements were taken, and the placement of each patient's MPFL graft tissue was determined to be anatomic or non-anatomic based on radiographic methods previously described in the literature. Each subject's electronic medical record was then reviewed, and clinical data was recorded. Finally, the clinical outcomes of each patient were compared to placement location of the MPFL graft tissue in their procedure. RESULTS: Thirteen patients were found to have anatomic MPFL graft tissue placement, and 14 non-anatomic. A significant post-operative difference was found between groups in the following parameters: WOMAC pain (anatomic mean = 85.71 ± 11.34, non-anatomic mean = 75.00 ± 26.35 p = 0.018), function (anatomic mean = 85.85 ± 9.96, non-anatomic mean = 79.09 ± 24.45, p = 0.017) and in KOOS symptom (anatomic mean = 75.63 ± 11.79, non-anatomic mean = 67.83 ± 22.40, p = 0.024), pain (anatomic mean = 77.54 ± 8.61, non-anatomic mean = 71.39 ± 25.18, p = 0.01), ADL (anatomic mean = 85.85 ± 9.97, non-anatomic mean = 79.09 ± 24.45, p = 0.017) and overall (anatomic mean = 74.61 ± 10.33, non-anatomic mean = 69.41 ± 24.25, p = 0.01) scores. No significant difference was observed for post-op instability (p = 0.290) or apprehension (p = 0.496), improvement in WOMAC or KOOS, 2-week, 6-week, or final 1-year range of motion, WOMAC stiffness, or KOOS sport/recreation or QOL. CONCLUSION: Within the range of graft placement values considered by this study, while no reduction in range of motion was seen, non-anatomic placement of MPFL graft tissue in MPFL reconstruction operations caused increased pain and decreased function, evidenced by post-operative KOOS and WOMAC scores. CLINICAL RELEVANCE: It seems that the pivotal step in MPFL reconstruction operations is ensuring correct patellofemoral tracking via intraoperative electrical femoral nerve stimulation. If this step of the procedure is performed correctly, non-anatomic placement will not limit range of motion, lead to continued apprehension, or affect the overall biomechanical functioning of the knee.

The effects of topical sodium cromoglicate on itch and flare in human skin induced by intradermal histamine: a randomised double-blind vehicle controlled intra-subject design trial.

BACKGROUND: Itch is a prominent feature of many skin diseases, particularly atopic dermatitis and cutaneous mastocytosis. Sodium cromoglicate (SCG), a chromone developed for the treatment of allergic disease has been shown to reduce the severity of itch when applied topically to subjects with atopic dermatitis. The aim of this study was to investigate whether topical sodium cromoglicate can reduce the severity of itch induced by intradermal histamine. METHODS: SCG was introduced into the skin of healthy volunteers both by iontophoresis and by topical application using a new 4% cutaneous emulsion (Altoderm™). The skin was then challenged with intradermal histamine. Measurements were made of severity of itch, size of wheal and flare and change in blood flux RESULTS: SCG significantly reduced the severity of itch (P = 0.0045) and flare (P = 0.0143) when delivered by iontophoresis. SCG 4% cutaneous emulsion significantly reduced severity of itch (P = 0.024) and flare (P = 0.015) in atopic subjects. Trend analysis showed increasing effect on itch with increased concentrations of SCG, which was significant (P = 0.046). There were no effects on wheal or blood flux. CONCLUSIONS: Topically applied SCG, administered in a new cutaneous emulsion base, significantly reduced the itch and flare caused by intradermal histamine. The effect was greatest in atopic subjects and increased with the concentration of SCG in the emulsion. TRIAL REGISTRATION: ISRCTN35671014.

Intestinal tumours induced in Apc(Min/+) mice by X-rays and neutrons.

PURPOSE: To compare the development of intestinal adenomas following neutron and X-ray exposure of Apc(Min/+) mice (Apc - adenomatous polyposis coli; Min - multiple intestinal neoplasia). MATERIALS AND METHODS: Adult mice were exposed to acute doses of X-rays or fission neutrons. Tumour counting was undertaken 200 days later and samples were taken for Loss of Heterozygosity (LOH) analysis. RESULTS: Tumour numbers (adenomas and microadenomas) increased by 1.4-fold, 1.7-fold, 2.7-fold and 9-fold, after 0.5, 1, 2 and 5 Gy X-rays, respectively, and by 2.4-fold and 5.7-fold, after 0.5 and 1 Gy fission neutrons, respectively. LOH analysis of tumours from neutron-exposed mice showed that 63% had lost Apc and 90% (cf. 53% in controls) had lost D18mit84, a marker for Epb4.1l4a/NBL4 (erythrocyte protein band 4.1-like 4a/novel band 4.1-like 4), known to be involved in the Wnt (wingless-related mouse mammary tumour virus integration site) pathway. Some tumours from neutron-exposed mice appeared to have homozygous loss of some chromosomal markers. CONCLUSIONS: X-ray or fission neutron irradiation results in strongly enhanced tumour multiplicities. Comparison of tumour yields indicated a low Relative Biological Effectiveness of around 2-8 for fission neutrons compared with X-rays. LOH in intestinal tumours from neutron-exposed mice appeared to be more complex than previously reported for tumours from X-irradiated mice.

Oral and topical sodium cromoglicate in the treatment of diffuse cutaneous mastocytosis in an infant.

Diffuse cutaneous mastocytosis (DCM) is a rare, severe, variant of cutaneous mastocytosis. The authors report the case of a male infant who developed maculae and maculopapulae on his legs and abdomen when aged 3.5 months, which spread to all body surfaces within weeks. Diagnosis of DCM was made at the age of 6 months when he had developed extensive bullous eruptions, generalised pruritus, flushing and abdominal pain. Treatment was started with oral dimethindine maleate. At the age of 18 months, oral sodium cromoglicate (SCG) was introduced. At the age of 23 months, additional treatment was started with a cutaneous emulsion containing 4% SCG. Continued treatment with oral dimethindine maleate, oral SCG with the dose maintained at 25 mg/kg/day, and SCG 4% cutaneous emulsion applied two to four times daily has resulted in a steady improvement of symptoms and skin appearance.

Diagnostic X-ray examinations and increased chromosome translocations: evidence from three studies.

Controversy regarding potential health risks from increased use of medical diagnostic radiologic examinations has come to public attention. We evaluated whether chromosome damage, specifically translocations, which are a potentially intermediate biomarker for cancer risk, was increased after exposure to diagnostic X-rays, with particular interest in the ionizing radiation dose-response below the level of approximately 50 mGy. Chromosome translocation frequency data from three separately conducted occupational studies of ionizing radiation were pooled together. Studies 1 and 2 included 79 and 150 medical radiologic technologists, respectively, and study 3 included 83 airline pilots and 50 university faculty members (total = 155 women and 207 men; mean age = 62 years, range 34-90). Information on personal history of radiographic examinations was collected from a detailed questionnaire. We computed a cumulative red bone marrow (RBM) dose score based on the numbers and types of X-ray examinations reported with 1 unit approximating 1 mGy. Poisson regression analyses were adjusted for age and laboratory method. Mean RBM dose scores were 49, 42, and 11 for Studies 1-3, respectively (overall mean = 33.5, range 0-303). Translocation frequencies significantly increased with increasing dose score (P < 0.001). Restricting the analysis to the lowest dose scores of under 50 did not materially change these results. We conclude that chromosome damage is associated with low levels of radiation exposure from diagnostic X-ray examinations, including dose scores of approximately 50 and lower, suggesting the possibility of long-term adverse health effects.

Oral and inhaled sodium cromoglicate in the management of systemic mastocytosis: a case report.

INTRODUCTION: Mastocytosis is a rare disease consisting of a group of disorders characterized by a pathologic increase in the number of mast cells in one or more organ system. Treatment is symptomatic. Oral sodium cromoglicate (SCG) is the only treatment licensed for the treatment of mastocytosis. In this case we report how in a mastocytosis patient being treated with H1 and H2 antihistamines, and oral sodium cromoglicate, the addition of inhaled sodium cromoglicate resulted in further improvement. This is the first report of this use of the drug in this disease. CASE PRESENTATION: The subject is a Caucasian woman aged 40 years. Symptoms of mastocytosis began when she was aged 13 years, but the diagnosis was not made until after her first pregnancy aged 33 years. Symptoms improved with H1 and H2 antihistamines, and oral sodium cromoglicate, but it required the addition of inhaled sodium cromoglicate to produce further improvement, specifically in the symptoms of bone pain, fatigue and headache. Doses of oral sodium cromoglicate had to be increased if challenged with a food to which the subject was sensitive. Doses of inhaled sodium cromoglicate had to be increased during the menstrual period. CONCLUSIONS: Patients suffering from the rare disease of mastocytosis have symptoms affecting many body systems. Symptoms result from the release of inflammatory mediators from mast cells. Sodium cromoglicate, a drug that reduces the release of mediators from mast cells, is effective in controlling gastrointestinal symptoms, but less effective in those affecting other body systems. In this case report we have shown that the addition of inhaled sodium cromoglicate controls the symptoms of bone pain, fatigue and headache and also that the doses have to be increased during the menstrual period.

Routine diagnostic X-ray examinations and increased frequency of chromosome translocations among U.S. radiologic technologists.

The U.S. population has nearly one radiographic examination per person per year, and concern about cancer risks associated with medical radiation has increased. Radiologic technologists were surveyed to determine whether their personal cumulative exposure to diagnostic X-rays was associated with increased frequencies of chromosome translocations, an established radiation biomarker and possible intermediary suggesting increased cancer risk. Within a large cohort of U.S. radiologic technologists, 150 provided a blood sample for whole chromosome painting and were interviewed about past X-ray examinations. The number and types of examinations reported were converted to a red bone marrow (RBM) dose score with units that approximated 1 mGy. The relationship between dose score and chromosome translocation frequency was assessed using Poisson regression. The estimated mean cumulative RBM radiation dose score was 49 (range, 0-303). After adjustment for age, translocation frequencies significantly increased with increasing RBM dose score with an estimate of 0.004 translocations per 100 cell equivalents per score unit (95% confidence interval, 0.002-0.007; P < 0.001). Removing extreme values or adjustment for gender, cigarette smoking, occupational radiation dose, allowing practice X-rays while training, work with radioisotopes, and radiotherapy for benign conditions did not affect the estimate. Cumulative radiation exposure from routine X-ray examinations was associated independently with increased chromosome damage, suggesting the possibility of elevated long-term health risks, including cancer. The slope estimate was consistent with expectation based on cytogenetic experience and atomic bomb survivor data.

Increased frequency of chromosome translocations associated with diagnostic x-ray examinations.

Informative studies of cancer risks associated with medical radiation are difficult to conduct owing to low radiation doses, poor recall of diagnostic X rays, and long intervals before cancers occur. Chromosome aberrations have been associated with increased cancer risk and translocations are a known radiation biomarker. Seventy-nine U.S. radiologic technologists were selected for blood collection, and translocations were enumerated by whole chromosome painting. We developed a dose score to the red bone marrow for medical radiation exposure from X-ray examinations reported by the technologists that they received as patients. Using Poisson regression, we analyzed translocations in relation to the dose scores. Each dose score unit approximated 1 mGy. The estimated mean cumulative red bone marrow radiation dose score was 42 (range 1-265). After adjustment for age, occupational radiation, and radiotherapy for benign conditions, translocation frequencies significantly increased with increasing red bone marrow dose score with an estimate of 0.007 translocations per 100 CEs per score unit (95% CI, 0.002 to 0.013; P = 0.01). Chromosome damage has been linked with elevated cancer risk, and we found that cumulative radiation exposure from medical X-ray examinations was associated with increased numbers of chromosome translocations.

International study of factors affecting human chromosome translocations.

Chromosome translocations in peripheral blood lymphocytes of normal, healthy humans increase with age, but the effects of gender, race, and cigarette smoking on background translocation yields have not been examined systematically. Further, the shape of the relationship between age and translocation frequency (TF) has not been definitively determined. We collected existing data from 16 laboratories in North America, Europe, and Asia on TFs measured in peripheral blood lymphocytes by fluorescence in situ hybridization whole chromosome painting among 1933 individuals. In Poisson regression models, age, ranging from newborns (cord blood) to 85 years, was strongly associated with TF and this relationship showed significant upward curvature at older ages versus a linear relationship (p<0.001). Ever smokers had significantly higher TFs than non-smokers (rate ratio (RR)=1.19, 95% confidence interval (CI), 1.09-1.30) and smoking modified the effect of age on TFs with a steeper age-related increase among ever smokers compared to non-smokers (p<0.001). TFs did not differ by gender. Interpreting an independent effect of race was difficult owing to laboratory variation. Our study is three times larger than any pooled effort to date, confirming a suspected curvilinear relationship of TF with age. The significant effect of cigarette smoking has not been observed with previous pooled studies of TF in humans. Our data provide stable estimates of background TF by age, gender, race, and smoking status and suggest an acceleration of chromosome damage above age 60 and among those with a history of smoking cigarettes.

Retrospective biodosimetry among United States radiologic technologists.

Measurement of chromosome translocations in peripheral blood lymphocytes has been used to quantify prior exposure to ionizing radiation, including for workers exposed to low, chronic doses. We assessed translocation frequencies in a subset of U.S. radiologic technologists to substantiate ionizing radiation dose estimates developed for 110,418 technologists who worked between 1916 and 1984. From 3,441 cohort members known to have begun working before 1950, we selected a sample of 152, stratified by estimated cumulative dose, over-sampling from higher-dose categories and excluding persons with a prior cancer diagnosis, a personal or family history of chromosomal instability disorders, or a current history of smoking. Estimates of film-badge dose ranged from less than 10 cSv to more than 30 cSv. Blood samples, obtained in 2004, were analyzed by fluorescence in situ hybridization (FISH) whole chromosome painting by simultaneously labeling chromosomes 1, 2 and 4 in red and 3, 5 and 6 in green. Translocations were scored in 1800 well-spread metaphase cells and expressed per 100 cell equivalents (CE) per person. Linear Poisson regression models with allowance for overdispersion were used to assess the relationship between estimated occupational red bone marrow absorbed dose in cGy and translocation frequency, adjusted for age, gender and estimated red bone marrow absorbed dose score from personal diagnostic procedures. We observed 0.09 excess translocations per 100 CE per cGy red bone marrow dose (95% CI: -0.01, 0.2; P = 0.07), which is similar to the expected estimate based on previous cytogenetic studies (0.05 excess translocations per 100 CE per cGy). Despite uncertainty in the estimates of occupational red bone marrow absorbed doses, we found good general agreement between the doses and translocation frequencies, lending support to the credibility of the dose assessment for this large cohort of U.S. radiologic technologists.

Direct single gene mutational events account for radiation-induced intestinal adenoma yields in Apc(Min/+) mice.

Data on the induction of small intestinal tumors, predominantly adenomas, by X radiation in Apc(Min/+) mice are reported. Comparison of these incidences with estimates of radiation-induced direct single gene mutation frequencies taken from the literature support the hypothesis that direct mutational loss of Apc+ is the sole requirement for initiation of adenoma. Furthermore, estimates of radiation-induced initiation of adenoma per target stem cell in this animal model are similar to or less than radiation-induced direct somatic gene mutation frequencies. Therefore, while the data reported here do not preclude a role for genomic instability in tumor progression, it is not necessary in this model to postulate the involvement of radiation-induced transmissible genomic instability in initiation of intestinal adenoma.

Adenoma multiplicity in irradiated Apc(Min) mice is modified by chromosome 16 segments from BALB/c.

Ionizing radiation (IR) is a well-characterized carcinogen in humans and mice. The BALB/c mouse strain is unusually sensitive to IR-induced tissue damage and cancer development in a range of organs, suggestive of a partial defect in DNA damage response. This has been confirmed by finding BALB/c-specific functional polymorphism in Prkdc, a gene on mouse chromosome 16 that encodes the catalytic subunit of DNA-dependent protein kinase. Prkdc(BALB) has been associated with increased susceptibility to IR-induced mammary and lymphatic neoplasia. Here, we provide evidence that chromosome 16 segments from BALB/c interact with Apc(Min) (multiple intestinal neoplasia) and specifically enhance IR-induced adenoma development in the upper part of the small intestine.

In vivo biostability of a poly(carbonate-urea)urethane graft.

In peripheral and coronary bypass surgery, the patency of prosthetic grafts is inferior to autologous vein, mainly due to intimal hyperplasia caused in part by compliance mismatch between rigid graft and elastic host artery. We have developed a compliant poly(carbonate-urea)urethane vascular graft "MyoLink" which was biostable in vitro degradation studies. To further investigate the biostability of this material, we report a long-term in vivo study on 8 beagle dogs (15+/-3 kg) implanted with this graft (ID 5mm) in the aorta-iliac position; three grafts were harvested at 18 months to assess short-term biodegradation, with one animal having died from an unrelated infection. The 4 remaining grafts were harvested at 36 months for analysis by: (1) histology, (2) compliance measurements and (3) environmental scanning electron microscopy (ESEM); gel permeation chromatography (GPC); attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) and radial tensile strength analysis. There was no infection or inflammation of the grafts or surrounding tissues. Histological analysis showed a well-developed neointima but only at the distal anastomosis. There were no significant differences in compliance pre- and post-implantation and no evidence of material curvature, radial expansion or chemical breakdown, ESEM and GPC showed no signs of degradation. Peak height analysis with ATR-FTIR of the 1740 cm(-1) (C=O of carbonate) and 1253 cm(-1) bands (C-O-C of CO-O-C) showed a loss of carbonate carbonyl but was not statistically significant. Radial tensile strength remained within batch release specifications.This polyurethane graft retains its compliance post-implantation, whilst exhibiting only a minor hydrolysis of the amorphous segment, confirming its biostability in vivo up to 3 years.

A major breakpoint cluster domain in murine radiation-induced acute myeloid leukemia.

Cytogenetic and molecular studies have provided evidence of the clustering of chromosome 2 deletion breakpoints in radiation-induced murine acute myeloid leukemia (AML). Moreover, clustering occurs in at least two fragile domains rich in telomere-like arrays. Here we describe a physical map of the distal breakpoint cluster and confirm the presence of inverted head-to-head telomeric sequence arrays. These potentially recombinogenic sequences were not, however, the direct focus for post-irradiation chromosome breakage in AML. Instead, the two arrays bordered a 2.5-kb sequence with properties expected of a nuclear matrix attachment region (MAR). The putative MAR co-localized in the fragile domain with genes important to the hemopoietic system (leukocyte tyrosine kinase, zinc finger protein 106, erythrocyte protein band 4.2, and beta(2)-microglobulin (beta2m)); the beta2m subdomain was a particular focus of breakage. On the basis of these and other data, we suggest that AML-associated chromosome 2 fragility in the mouse is a consequence of domain-specific fragility in genomic domains containing numerous genes critical to the hemopoietic system. Recorded with the permission of the controller of Her Majesty's Stationery Office. Published by Wiley-Liss, Inc.

Functional evidence from microcell-mediated chromosome transfer of myeloid leukemia suppressor genes on human chromosomes 7 and 11.

The long arm of human chromosome 7 between 7q22 and 7q36 has been identified as a region harboring one or more tumor-suppressor genes (TSGs) inactivated in acute myeloid leukemia (AML). Additional TSGs mapping to other chromosomes may well be involved in the etiology of this disease. For example, experiments using a mouse model system have indicated the possible presence of an AML TSG at 11p11-12. Microcell-mediated chromosome transfer (MMCT) has been used to introduce human chromosomes 7 and 11 into a murine myeloid leukemia cell line. A proportion of MMCT hybrid clones containing either whole chromosome 7 or fragments of chromosome 11 showed a significant delay in leukemogenic onset when injected into syngeneic mice. Screening of hybrid clones did not associate any human microsatellite markers with decreased leukemogenic potential in vivo. However, preliminary evidence was obtained of allelic loss at chromosomal regions homologous with human 7q22 in murine F1 hybrid AMLs. Our data provide functional evidence of AML-associated TSGs localized to human chromosomes 7 and 11 in support of previously published studies on cytogenetic and allelic losses associated with AML development.