DSC Perfusion MRI-Derived Fractional Tumor Burden and Relative CBV Differentiate Tumor Progression and Radiation Necrosis in Brain Metastases Treated with Stereotactic Radiosurgery.

BACKGROUND AND PURPOSE: Differentiation between tumor and radiation necrosis in patients with brain metastases treated with stereotactic radiosurgery is challenging. We hypothesized that MR perfusion and metabolic metrics can differentiate radiation necrosis from progressive tumor in this setting. MATERIALS AND METHODS: We retrospectively evaluated MRIs comprising DSC, dynamic contrast-enhanced, and arterial spin-labeling perfusion imaging in subjects with brain metastases previously treated with stereotactic radiosurgery. For each lesion, we obtained the mean normalized and standardized relative CBV and fractional tumor burden, volume transfer constant, and normalized maximum CBF, as well as the maximum standardized uptake value in a subset of subjects who underwent FDG-PET. Relative CBV thresholds of 1 and 1.75 were used to define low and high fractional tumor burden. RESULTS: Thirty subjects with 37 lesions (20 radiation necrosis, 17 tumor) were included. Compared with radiation necrosis, tumor had increased mean normalized and standardized relative CBV (P = .002) and high fractional tumor burden (normalized, P = .005; standardized, P = .003) and decreased low fractional tumor burden (normalized, P = .03; standardized, P = .01). The area under the curve showed that relative CBV (normalized = 0.80; standardized = 0.79) and high fractional tumor burden (normalized = 0.77; standardized = 0.78) performed the best to discriminate tumor and radiation necrosis. For tumor prediction, the normalized relative CBV cutoff of ≥1.75 yielded a sensitivity of 76.5% and specificity of 70.0%, while the standardized cutoff of ≥1.75 yielded a sensitivity of 41.2% and specificity of 95.0%. No significance was found with the volume transfer constant, normalized CBF, and standardized uptake value. CONCLUSIONS: Increased relative CBV and high fractional tumor burden (defined by a threshold relative CBV of ≥1.75) best differentiated tumor from radiation necrosis in subjects with brain metastases treated with stereotactic radiosurgery. Performance of normalized and standardized approaches was similar.

Mercury distribution and speciation in two lagoons with different pollution and eutrophication conditions in Taiwan.

This study explored biogeochemical processes controlling the distribution of mercury (Hg) species in two lagoons with different pollution and eutrophication conditions in southwestern Taiwan. The eutrophication and pollution levels were higher in the Dapeng Bay than in the Chiku Lagoon, engendering a higher particulate Hg concentration and enrichment factor in the Dapeng Bay. The concentration range of total dissolved Hg (HgTD) and reactive Hg (HgR) was comparable between the lagoons, but the concentration of particulate Hg (HgP) was higher in the Dapeng Bay. HgR and HgTD abundance was primarily controlled by the availability of dissolved oxygen (DO) and biological absorption. In addition to pollution (which elevated HgP concentration), biological absorption and/or adsorption rather than lithogenic processes more likely regulated the HgP concentration. The effect of Hg pollution may superimpose on that of DO on the distributions of HgR and HgTD and may enhance HgP formation in the Dapeng Bay.

Predicting Hepatic Steatosis in Living Liver Donors Via Controlled Attenuation Parameter.

BACKGROUND: Hepatic steatosis (HS) can cause substantial problems for both donors and recipients in living donor liver transplantation. The controlled attenuation parameter (CAP) is a noninvasive method of measuring HS using a process based on transient elastography. AIM: To evaluate the accuracy of CAP in quantifying HS during living donor liver transplantation. METHODS: A total of 54 liver donors who received CAP and intraoperative liver biopsy (LB) were enrolled in this study. The performance of CAP compared with LB for diagnosing HS was assessed using areas under receiver operating characteristic curves. HS was defined by the presence of steatosis in >5% of hepatocytes. RESULTS: No HS was found in 47 donors, while the remaining 7 donors showed HS ranging from 10% to 30%. Using CAP, the area under receiver operating characteristic curve was 0.96 (95% CI, 0.91-1; P < .001) for HS; the optimal cutoff value for HS was 257 dB/m (sensitivity: 100%, specificity: 89.4%, positive predictive value: 58.3%, negative predictive value: 100%). Among the 42 candidates with CAP <257 dB/m, none had HS, while of the 12 candidates with CAP ≥257 dB/m, 7 had HS. In a multivariate linear regression analyses, body mass index (ß = 0.71, P < .001) was found to be independently associated with CAP in those without HS. CONCLUSIONS: CAP might be a promising tool to exclude HS in East Asian living liver donors. Body mass index was found to be independently associated with CAP values in those without HS.

Comparison of molecular diagnosis with serum markers and synovial fluid analysis in patients with prosthetic joint infection.

AIMS: The aim of this study was to compare the results of 16S/28S rRNA sequencing with the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, and synovial fluid analysis in the diagnosis of prosthetic joint infection (PJI). PATIENTS AND METHODS: Between September 2015 and August 2016, 214 consecutive patients were enrolled. In the study population, there were 25 patients with a PJI and 189 controls. Of the PJI patients, 14 (56%) were women, and the mean age at the time of diagnosis was 65 years (38 to 83). The ESR and CRP levels were measured, and synovial fluid specimens were collected prospectively. Synovial fluid was subjected to reverse transcription polymerase chain reaction (RT-PCR)/sequence analysis targeting the 16S/28S rRNA, and to conventional culture. Laboratory personnel who were blind to the clinical information performed all tests. The diagnosis of PJI was based on the criteria of the Musculoskeletal Infection Society. RESULTS: A total of 25 patients had a confirmed PJI. In 20 cases of monomicrobial PJI, the PCR products could be perfectly matched with the 16S/28S rRNA genes specific for different species of bacteria provided by sequence analysis. Of the five polymicrobial cases of PJI, 16S/28S rRNA PCR sequence analysis failed to identify the concordant bacteria species. In the 189 control patients, there was one false-positive RT-PCR result. The sensitivity and specificity of the molecular diagnosis method were 100% (95% confidence interval (CI) 85.7 to 100) and 99.5% (95% CI 97.1 to 99.9), respectively, whereas the positive and negative predictive values of PCR were 96.1% (95% CI 79.6 to 99.9) and 100% (95% CI 98.1 to 100), respectively. The PCR results were significantly better than serological diagnostic methods (p = 0.004 and p = 0.010 for ESR and CRP, respectively), the synovial fluid white blood cell (WBC) count (p = 0.036), and percentage of polymorphonuclear cells (PMN%) (p = 0.014). CONCLUSION: Stepwise RT-PCR and sequence analysis of the 16S/28S rRNA carried out under stringent laboratory conditions achieved highly sensitive and specific results for the differentiation between aseptic and septic joints undergoing arthroplasty. Sequence analysis successfully identified bacterial strains in monomicrobial infections but failed to identify molecular targets in polymicrobial infections. Further refinement of the protocols to identify the bacteria in polymicrobial infections is needed. Cite this article: Bone Joint J 2018;100-B:1345-51.

A regime of two intravenous injections of tranexamic acid reduces blood loss in minimally invasive total hip arthroplasty: a prospective randomised double-blind study.

Tranexamic acid (TXA), an inhibitor of fibrinolysis, reduces blood loss after total knee arthroplasty. However, its effect on minimally invasive total hip arthroplasty (THA) is not clear. We performed a prospective, randomised double-blind study to evaluate the effect of two intravenous injections of TXA on blood loss in patients undergoing minimally invasive THA. In total, 60 patients (35 women and 25 men with a mean age of 58.1 years; 17 to 84) who underwent unilateral minimally invasive uncemented THA were randomly divided into the study group (30 patients, 20 women and ten men with a mean age of 56.5 years; 17 to 79) that received two intravenous injections 1 g of TXA pre- and post-operatively (TXA group), and a placebo group (30 patients, 15 women and 15 men with a mean age of 59.5 years; 23 to 84). We compared the peri-operative blood loss of the two groups. Actual blood loss was calculated from the maximum reduction in the level of haemoglobin. All patients were followed clinically for the presence of venous thromboembolism. The TXA group had a lower mean intra-operative blood loss of 441 ml (150 to 800) versus 615 ml (50 to 1580) in the placebo (p = 0.044), lower mean post-operative blood loss (285 ml (120 to 570) versus 392 ml (126 to 660) (p = 0.002), lower mean total blood loss (1070 ml (688 to 1478) versus 1337 ml (495 to 2238) (p = 0.004) and lower requirement for transfusion (p = 0.021). No patients in either group had symptoms of venous thromboembolism or wound complications. This prospective, randomised controlled study showed that a regimen of two intravenous injections of 1 g TXA is effective for blood conservation after minimally invasive THA.

Gorgonian coral (Junceella juncea and Junceella fragilis) oocyte chilling sensitivity in the context of adenosine triphosphate response (ATP).

Gorgonian corals are suffering continued decline in population and reproductive ability because of environmental changes. Cryopreservation can play an important role in ex situ conservation for these corals. In the present study, oocyte chilling sensitivity in the context of adenosine triphosphate (ATP) response in two gorgonian species (Junceella juncea and Junceella fragilis) and the effectiveness of cryoprotectants in protecting coral oocytes from chilling injury were studied in an attempt to develop protocols for their cryopreservation. Oocytes of two gorgonian corals were exposed to methanol (1 M, 2 M) and EG (1 M) at 5, 0 and -5 degree C for up to 216 hours, and ATP levels in oocytes were then determined. ATP levels decreased gradually with exposure time and 1M methanol was more effective in protecting oocytes from chilling injury than other cryoprotectant treatments tested. J. juncea oocytes were less sensitive to chilling than J. fragilis oocytes. This study provided useful information for development of cryopreservtion protocols for the two gorgonian coral oocytes.

100 GHz ultra-wideband (UWB) fiber-to-the-antenna (FTTA) system for in-building and in-home networks.

Fiber-to-the-antenna (FTTA) system can be a cost-effective technique for distributing high frequency signals from the head-end office to a number of remote antenna units via passive optical splitter and propagating through low-loss and low-cost optical fibers. Here, we experimentally demonstrate an optical ultra-wideband (UWB) - impulse radio (IR) FTTA system for in-building and in-home applications. The optical UWB-IR wireless link is operated in the W-band (75 GHz - 110 GHz) using our developed near-ballistic unitraveling-carrier photodiode based photonic transmitter (PT) and a 10 GHz mode-locked laser. 2.5 Gb/s UWB-IR FTTA systems with 1,024 high split-ratio and transmission over 300 m optical fiber are demonstrated using direct PT modulation.

First Report of Tomato spotted wilt virus in Sweet Pepper in Taiwan.

A new disorder on pepper showing symptoms of chlorosis and chlorotic spots on leaves was observed in sweet pepper (Capsicum annuum cv. Andalus) fields in Ren-Ai Township, Nantou County in July, 2009. The disorder occurred in more than 30% of the pepper plants, with a height of approximately 40 cm (1.5 feet), which was approximately one-half the size of the asymptomatic ones. Symptomatic plants bore much smaller fruits with abnormal shapes. Three symptomatic sweet pepper plants were collected and tested for potential viruses. Reverse transcription (RT)-PCR was performed for the detection using three degenerate primer pairs, gL3637/gL4435c for tospoviruses (2), Hrp5/Pot1 for potyviruses (1,3), and Tob-Uni1/Tob-Uni2 for tobamoviruses (4), and specific primers, FJJ2001-7/FJJ2001-8 (5'-TATGTCCATGGACAAATCCGAATCA and 5'-TCTCTGGATCCACGAGTTCAAACTGGGAG) for the coat protein gene of Cucumber mosaic virus (CMV). An 819-nt DNA fragment containing the partial L RNA of tospovirus was amplified from the total RNA isolated from each of these three samples by RT-PCR with primer pair gL3637/gL4435c. One amplified fragment was cloned and sequenced. A homology search in GenBank indicated that the new pepper-infecting virus in Taiwan was Tomato spotted wilt virus (TSWV) since the partial L RNA shared more than 94.5% nucleotide and 98.2% amino acid identity with five TSWV isolates (Accession Nos. AB190813, AB198742, AY070218, D10066, and NC_002052). No DNA fragment was obtained by RT-PCR using primer pairs for CMV, potyviruses, or tobamoviruses. A virus culture (TwPep1) isolated from one of the symptomatic sweet pepper plants was then established in Nicotiana tabacum cv. White Burley and N. benthamiana through triple single-lesion isolation. TWPep1 reacted positively only to the antiserum against TSWV by indirect-ELISA but not to those of Watermelon silver mottle virus, Capsicum chlorosis virus, Tobacco mosaic virus, Tomato mosaic virus, and CMV. Partial L RNA and the full-length nucleocapsid (N) gene of TWPep1 were obtained by RT-PCR with primer pairs gL3637/gL4435c and FJJ2002-74/FJJ2002-75 (5'-GCGCGCGGATCCTAATTTAACTTACARCTGCT 5'-TGCTGCCTCGAGCATACGGTCAAAGCATATAA), respectively. The 819-nt L RNA conserved region of TwPep1 (Accession No. GU222652) shared 94.4 to 97.7% nucleotide and 98.2 to 100% amino acid identity with those available in GenBank. The 777-bp N gene of TwPep1 (Accession No. GU222651) shared 96.7 to 99.1% nucleotide and 97.3 to 99.6% amino acid identity with 37 TSWV isolates available in GenBank. Sequence comparisons indicated that TwPep1 is an isolate of TSWV. TSWV was later detected by RT-PCR in all 10 symptomatic samples of sweet pepper plants collected from five fields in August 2009. To our knowledge, this is the first report of TSWV in sweet pepper in Taiwan. This is also the first demonstration of isolation and characterization of TSWV in Taiwan although TSWV was once detected in lisianthus (Eustoma rusellianum) by RT-PCR (1) but the isolation was not successful then. The occurrence of TSWV in pepper will have a direct economic impact on the important vegetable and floral industry in Taiwan because TSWV reportedly comprises a wide host range. References: (1) C. C. Chen et al. Bot. Stud. 947:369, 2006. (2) F. H. Chu et al. Phytopathology 91:361, 2001. (3) D. Colinet and J. Kummert. J. Virol. Methods 45:149, 1993. (4) B. Letschert et al. J. Virol. Methods 106:1, 2002.

Use of an adenosine triphosphate assay, and simultaneous staining with fluorescein diacetate and propidium iodide, to evaluate the effects of cryoprotectants on hard coral (Echinopora spp.) oocytes.

The objective was to examine the effects of cryoprotectants on oocytes of hard corals (Echinopora spp.) to obtain basic knowledge for cryopreservation procedures. Oocytes were exposed to various concentrations of cryoprotectants (0.25 to 5.0M) for 20 min at room temperature (25 degrees C). Two tests were used to assess ovarian follicle viability: fluorescein diacetate (FDA)+propidium iodide (PI) staining, and adenosine triphosphate (ATP) assay. Both FDA+PI staining and ATP assay indicated that cryoprotectant toxicity to oocytes increased in the order methanol, dimethyl sulfoxide (DMSO), propylene glycol (PG), and ethylene glycol (EG). The no observed effect concentrations for Echinopora spp. oocytes were 1.0, 0.5, 0.25, and 0.25 M for methanol, DMSO, PG, and EG, respectively, when assessed with FDA+PI. The ATP assay was more sensitive than FDA+PI staining (P<0.05). Oocyte viability after 1.0M methanol, DMSO, EG, or PG treatment for 20 min at room temperature assessed with FDA+PI tests and ATP assay were 88.9+/-3.1% and 72.2+/-4.4%, 66.2+/-5.0% and 23.2+/-4.9%, 58.9+/-5.4% and 1.1+/-0.7%, and 49.1+/-5.1% and 0.9+/-0.5%, respectively. We inferred that the ATP assay was a valuable measure of cellular injury after cryoprotectant incubation. The results of this study provided a basis for development of protocols to cryopreserve coral oocytes.

Amoxicillin resistance with beta-lactamase production in Helicobacter pylori.

BACKGROUND: Amoxicillin-resistant Helicobacter pylori with minimal inhibitory concentration (MIC) >or= 256 mg L(-1) was isolated from a gastritis patient. The aims were to investigate the mechanism of high-level amoxicillin resistance in H. pylori. MATERIALS AND METHODS: The beta-lactamase production was determined by means of nitrocefin sticks and the presence of gene encoding the beta-lactam antibiotic resistance enzyme TEM beta-lactamase was analysed by polymerase chain reaction (PCR), sequencing and dot-blot hybridization. Sequencing analysis of pbp1A gene was performed and amoxicillin-susceptible isolate was transformed with pbp1A PCR products from the resistant isolate. The expression of hefC efflux system was analysed using real-time quantitative PCR. RESULTS: Activity of beta-lactamase was detected. Sequence analysis showed that the PCR product derived from H. pylori 3778 was identical to the bla(TEM-1) (GenBank accession EU726527). Dot-blot hybridization confirmed the presence of beta-lactamase gene bla(TEM-1.) By transformation of PCR product of mutated pbp1A gene from H. pylori 3778 into amoxicillin-susceptible strain showed that substitutions in Thr(556)-->Ser, Lys(648)-->Gln, Arg(649)-->Lys and Arg(656)-->Pro contribute to low-level amoxicillin resistance. The MIC of amoxicillin for the transformants was 0.75 mg L(-1). Over-expression of hefC was not found. CONCLUSIONS: High-level amoxicillin resistance is associated with beta-lactamase production in H. pylori. Low-level amoxicillin resistance is linked to a point mutation on pbp1A. Because H. pylori can exchange DNA through natural transformation, spreading of bla(TEM-1) amoxicillin resistance gene among H. pylori is a potential threat when treating H. pylori infection.

Increased bioavailability of a transdermal application of a nano-sized emulsion preparation.

The aim of this study was to compare the transdermal application of a nano-sized emulsion versus a micron-sized emulsion preparation of delta tocopherol as it relates to particle size and bioavailability. Two separate experiments were performed using seven F1B Syrian Golden hamsters, 1 week apart. Each emulsion preparation consisted of canola oil, polysorbate 80, deionized water and delta tocopherol; the only difference between the two preparations was processing the nano-sized emulsion with the Microfluidizer Processor. Both were formulated into a cream and applied to the shaven dorsal area. The particle size of the micron-sized emulsion preparation was 2788 nm compared to 65 nm for the nano-sized emulsion formulation. Two hours post-application, hamsters that were applied the nano-sized emulsion had a 36-fold significant increase of plasma delta tocopherol, where as hamsters that were applied the micron-sized emulsion only had a 9-fold significant increase, compared to baseline, respectively. At 3h post-application, plasma delta tocopherol had significantly increased 68-fold for hamsters applied the nano-sized emulsion, whereas only an 11-fold significant increase was observed in hamsters applied the micron-sized emulsion, compared to baseline, respectively. Significant differences were also observed between the nano-sized and micron-sized emulsion at 2 and 3h post-application. This study suggests that nano-sized emulsions significantly increase the bioavailability of transdermally applied delta tocopherol.

Detection and quantification of glucuro- and sulfoconjugated metabolites in human urine following oral administration of xenobiotic 19-norsteroids.

Recently, the endogenous origin of nandrolone (19-nortestosterone) and other 19-norsteroids has been a focus of research in the field of drug testing in sport. In the present study, we investigated metabolites conjugated to a glucuronic acid and to a sulfuric acid in urine following administration of four xenobiotic 19-norsteroids. Adult male volunteers administered a single oral dose (10 mg) of each of four 19-norsteroids. Urinary samples collected from 0 to 120 h were subjected to methanolysis and beta-glucuronidase hydrolysis and were derivatized by N-methyl-N-trimethylsilyltrifluoroacetamide (MSTFA) before gas chromatography-mass spectrometry analysis. We confirmed that 19-norandrosterone (19-NA) and 19-noretiocholanolone (19-NE) were present in both glucuronide (g) and sulfate (s) conjugates and 19-norepiandrosterone (19-NEA) was excreted exclusively as a sulfate fraction in urine of all 19-norsteroids tested. The overall levels of the three metabolites can be ranked as follows: 19-NA(g+s)>19-NE(g+s)>19-NEA(s). The concentration profiles of these three metabolites in urine peaked between 2 to 12h post-administration and declined thereafter until approximately 72-96 h. 19-NA was most prominent throughout the first 24 h post-administration, except for a case in which an inverse relationship was found after 6h post-administration of nandrolone. Furthermore, we found that sulfate conjugates were present in both 19-NA and 19-NE metabolites in urine of all 19-norsteroids tested. The averaged total amounts of metabolites (i.e. 19-NA(s+g)+19-NE(s+g)+19-NEA(s)) excreted in urine were 38.6, 42.9, 48.3 and 21.6% for nandrolone, 19-nor-4-androsten-3,17-dione, 19-nor-4-androsten-3beta,17beta-diol and 19-nor-5-androstene-3beta,17beta-diol, respectively. Results from the excretion studies demonstrate significance of sulfate-conjugated metabolites on interpretation of misuse of the 19-norsteroids.

Interaction between cigarette, alcohol and betel nut use on esophageal cancer risk in Taiwan.

OBJECTIVE: In 2003 esophageal cancer was the sixth leading cause of death among men in Taiwan, but it is the fastest increasing (70%) alimentary tract cancer. The aim of this study was to investigate the impact of different habits of betel nut chewing on esophageal squamous cell carcinoma (SCC) and its interaction with cigarette use and alcohol consumption. MATERIALS AND METHODS: All 165 cases were pathologically proven esophageal SCC patients (all male, mean age = 56.0, range = 35-92 years) diagnosed by biopsy during gastroendoscopic examinations. The control group comprised 255 subjects (all male, mean age = 54.8, range = 40-92 years) selected from patients who had visited the Otolaryngology Outpatient or Inpatient Department of KMUH owing to a benign lesion over this field. All were interviewed to collect demographic and substance use information by a trained interviewer using a standardized questionnaire. RESULTS: Smoking (aOR = 5.4, 95% CI = 2.4-12.9, PAR = 72%), alcoholic beverage drinking (aOR = 17.6, 95% CI = 9.3-35.2, PAR = 76%) and low education level are independent risk factors for esophageal cancer. Although betel nut chewers only had a borderline significant higher risk than nonchewers (aOR = 1.7; 95% CI = 0.8-3.1), those who chewed with a piece of betel inflorescence (aOR = 4.2, 95% CI = 1.4-16.0) and swallow betel-quid juice (aOR = 3.3, 95% CI = 1.3-9.3) had a significant higher risk. Significant dose-response effects were found in daily quantity of drinking and smoking. There is a synergistic effect of these three substances on the development of esophageal cancer. CONCLUSION: Betel nut chewing plays a relevant role in the development of esophageal SCC but adds to the carcinogenetic effect of smoking and alcohol drinking. Direct mucosal contact of betel juice may contribute to its carcinogenesis.

Synthesis and biological activity of some known and putative duloxetine metabolites.

Several putative phase I duloxetine metabolites, 4-hydroxy-, 5-hydroxy-, 6-hydroxy-, 5-hydroxy-6-methoxy-, 6-hydroxy-5-methoxy-, 5,6-dihydroxy-, and 4,6-dihydroxyduloxetine were synthesized, and their phase II metabolite as glucuronide or sulfate conjugates were also synthesized. Their in vitro binding activities were compared to that of parent compound duloxetine.

Metabolism, excretion, and pharmacokinetics of duloxetine in healthy human subjects.

Duloxetine is a potent and balanced dual inhibitor of serotonin and norepinephrine reuptake being investigated for the treatment of depression and urinary incontinence. The disposition of duloxetine was studied in four healthy human subjects after a single 20.2-mg (100.6 microCi) oral dose of [14C]duloxetine in an enteric-coated tablet. The mean total recovery of radioactivity (+/- S.E.M.) after 312 h was 90.5% (+/-0.4%) with 72.0% (+/-1.1%) excreted in the urine. Duloxetine was extensively metabolized to numerous metabolites primarily excreted into the urine in the conjugated form. The major biotransformation pathways for duloxetine involved oxidation of the naphthyl ring at either the 4-, 5-, or 6-positions followed by further oxidation, methylation, and/or conjugation. The major metabolites found in plasma were glucuronide conjugates of the following: 4-hydroxy duloxetine (M6), 6-hydroxy-5-methoxy duloxetine (M10), 4, 6-dihydroxy duloxetine (M9), and a sulfate conjugate of 5-hydroxy-6-methoxy duloxetine (M7). The major metabolites found in plasma were also found in the urine, but the urine contained many additional metabolites. In addition to duloxetine, 4-hydroxy duloxetine (M14) and an unidentified polar metabolite were observed in feces. Following [14C]duloxetine administration, Cmax was reached at a median of 6 h for both duloxetine and total radioactivity. Duloxetine accounted for less than 3% of the circulating radioactivity based on mean area under the curve values. The elimination half-life of total radioactivity (120 h) was substantially longer than that of duloxetine (10.3 h).

Chromosome-wide distribution of haplotype blocks and the role of recombination hot spots.

Recent studies of human populations suggest that the genome consists of chromosome segments that are ancestrally conserved ('haplotype blocks'; refs. 1-3) and have discrete boundaries defined by recombination hot spots. Using publicly available genetic markers, we have constructed a first-generation haplotype map of chromosome 19. As expected for this marker density, approximately one-third of the chromosome is encompassed within haplotype blocks. Evolutionary modeling of the data indicates that recombination hot spots are not required to explain most of the observed blocks, providing that marker ascertainment and the observed marker spacing are considered. In contrast, several long blocks are inconsistent with our evolutionary models, and different mechanisms could explain their origins.

Partitioning an object-oriented terminology schema.

Controlled medical terminologies are increasingly becoming strategic components of various healthcare enterprises. However, the typical medical terminology can be difficult to exploit due to its extensive size and high density. The schema of a medical terminology offered by an object-oriented representation is a valuable tool in providing an abstract view of the terminology, enhancing comprehensibility and making it more usable. However, schemas themselves can be large and unwieldy. We present a methodology for partitioning a medical terminology schema into manageably sized fragments that promote increased comprehension. Our methodology has a refinement process for the subclass hierarchy of the terminology schema. The methodology is carried out by a medical domain expert in conjunction with a computer. The expert is guided by a set of three modeling rules, which guarantee that the resulting partitioned schema consists of a forest of trees. This makes it easier to understand and consequently use the medical terminology. The application of our methodology to the schema of the Medical Entities Dictionary (MED) is presented.

AMF1 (GPS2) modulates p53 transactivation.

We have reported that the papillomavirus E2 protein binds the nuclear factor AMF1 (also called G-protein pathway suppressor 2 or GPS2) and that their interaction is necessary for transcriptional activation by E2. It has also been shown that AMF1 can influence the activity of cellular transcription factors. These observations led us to test whether AMF1 regulates the functions of p53, a critical transcriptional activator that integrates stress signals and regulates cell cycle and programmed cell death. We report that AMF1 associates with p53 in vivo and in vitro and facilitates the p53 response by augmenting p53-dependent transcription. Overexpression of AMF1 in U2OS cells increases basal level p21(WAF1/CIP1) expression and causes a G(1) arrest. U2OS cells stably overexpressing AMF1 show increased apoptosis upon exposure to UV irradiation. These data demonstrate that AMF1 modulates p53 activities.