Accurate diagnosis of colorectal cancer based on histopathology images using artificial intelligence.

BACKGROUND: Accurate and robust pathological image analysis for colorectal cancer (CRC) diagnosis is time-consuming and knowledge-intensive, but is essential for CRC patients' treatment. The current heavy workload of pathologists in clinics/hospitals may easily lead to unconscious misdiagnosis of CRC based on daily image analyses. METHODS: Based on a state-of-the-art transfer-learned deep convolutional neural network in artificial intelligence (AI), we proposed a novel patch aggregation strategy for clinic CRC diagnosis using weakly labeled pathological whole-slide image (WSI) patches. This approach was trained and validated using an unprecedented and enormously large number of 170,099 patches, > 14,680 WSIs, from > 9631 subjects that covered diverse and representative clinical cases from multi-independent-sources across China, the USA, and Germany. RESULTS: Our innovative AI tool consistently and nearly perfectly agreed with (average Kappa statistic 0.896) and even often better than most of the experienced expert pathologists when tested in diagnosing CRC WSIs from multicenters. The average area under the receiver operating characteristics curve (AUC) of AI was greater than that of the pathologists (0.988 vs 0.970) and achieved the best performance among the application of other AI methods to CRC diagnosis. Our AI-generated heatmap highlights the image regions of cancer tissue/cells. CONCLUSIONS: This first-ever generalizable AI system can handle large amounts of WSIs consistently and robustly without potential bias due to fatigue commonly experienced by clinical pathologists. It will drastically alleviate the heavy clinical burden of daily pathology diagnosis and improve the treatment for CRC patients. This tool is generalizable to other cancer diagnosis based on image recognition.

Tra2ß protects against the degeneration of chondrocytes by inhibiting chondrocyte apoptosis via activating the PI3K/Akt signaling pathway.

OBJECTIVE: Osteoarthritis (OA) is a common disease in the elderly and seriously affects the quality of life of patients. Tra2ß is a protein that has been found to activate PI3K/Akt in recent years. The purpose of this study was to explore the protective effects of Tra2ß on chondrocytes and its mechanisms. PATIENTS AND METHODS: The expression of Tra2ß in knee cartilage tissue of patients with OA and normal people was compared. In addition, human primary chondrocytes were cultured, the expression of Tra2ß in chondrocytes by cell transfection was changed, and its effects on extracellular matrix, inflammation, and apoptosis in chondrocytes were examined. LY294002 was also used to inhibit the activity of PI3K/Akt signaling pathway to verify the mechanism of Tra2ß to protect chondrocytes. RESULTS: The expression of Tra2ß in the cartilage tissue of the OA group was significantly lower than that of the control group, and the IL-1ß-induced chondrocytes also expressed the lower Tra2ß. The overexpression of Tra2ß increased the expression of extracellular matrix collagen II and decreased the expressions of MMP3/13, inflammatory factors (IL-6, IL-8 and TNF-α), and apoptotic factors (caspase3/9, Bax). In addition, the overexpression of Tra2ß also increased expression and phosphorylation of PI3K and Akt. However, LY294002 attenuated the protective effect of Tra2ß on chondrocytes by inhibiting the PI3K/Akt signaling pathway. CONCLUSIONS: Tra2ß activates the PI3K/Akt signaling pathway, reduces the degradation of extracellular matrix of chondrocytes, reduces the level of inflammation and apoptosis of chondrocytes, and thus, plays a role in the treatment of OA.

Effects of miR-26a/miR-146a/miR-31 on airway inflammation of asthma mice and asthma children.

OBJECTIVE: This study detected the expressions of microRNA-26a (miR-26a), miR-146a and miR-31 in lung tissues and BALF (bronchoalveolar lavage fluid) of asthma mice and children. Besides, cytokine levels of interleukin-5 (IL-5), IL-8, IL-12 and tumor necrosis factor-α (TNF-α) were detected as well. We aim to provide an experimental basis for clinical treatment of asthma. PATIENTS AND METHODS: Forty female BALB/c mice were randomly assigned into control group and asthma group, respectively. Mice in asthma group (n=20) were immunized by intraperitoneal injection of OVA (ovalbumin) and provoked by atomization inhalation of OVA from the 15th day for 10 days. Mice in control group (n=20) were immunized and provoked with isodose saline during the same period. At the 26th day, mice were sacrificed for collecting lung tissues and BALF. Besides, we enrolled 17 cases of asthma children and 13 cases of children with airway foreign body as controls. BALF of each subject was collected. Total cellular score and differential counting in BALF were recorded. Expression levels of miR-26a, miR-146a, and miR-31 were detected by reverse transcription-polymerase chain reaction (RT-PCR). Levels of IL-5, IL-8, IL-12, and TNF-α were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: The total cellular score in BALF of asthma mice and asthma children was higher than that of controls (p<0.05). Percentages of eosinophils, neutrophils, and lymphocytes in BALF of asthma mice and asthma children were higher than those of controls, whereas the percentage of macrophages was lower (p<0.05). Levels of IL-5, IL-8, IL-12, and TNF-α in lung tissues of asthma mice were markedly elevated compared with those of controls (p<0.05). Similarly, levels of IL-5, IL-8, IL-12, and TNF-α were higher in BALF of asthma children than controls (p<0.05). RT-PCR data showed higher mRNA levels of miR-26a, miR-146a, and miR-31 in lung tissues of asthma mice than controls (p<0.05). The mRNA levels of miR-26a, miR-146a, and miR-31 in BALF of asthma children were highly expressed compared with those of controls as well (p<0.05). CONCLUSIONS: MiR-26a, miR-146a, and miR-31 are involved in asthma progression mainly through regulating inflammatory factors and cells.

Calcium intake and hypertension among obese adults in United States: associations and implications explored.

The relationship between calcium intake and hypertension is receiving increased research attention. The prevalence of hypertension is high among the obese populations. Calcium is a mineral that influences blood pressure. The aim of the study was to examine the association between calcium intake and hypertension in a large nationally representative sample of obese American adults. A total of 14,408 obese adults aged 20 years or older were obtained from the 1999-2010 National Health and Nutrition Examination Survey. Analysis of variance and linear regression models were used to examine relationships between calcium intake and systolic blood pressure (SBP) as well as diastolic blood pressure (DBP). Multiple logistic regression models were used to examine the association between calcium intake and hypertension after adjusting for potential confounders and interactions, including: age, race, education level, alcohol use, smoking, diabetes status, sodium intake and potassium intake. Calcium intake was significantly lower for the hypertensive group compared with the normotensive group (P<0.0001), especially among those obese female young adults aged 20-44 years and among non-diabetic obese adults. Based on ordinary linear regression analysis, a significant inverse relationship was detected, SBP and DBP decreased if calcium intake increased (SBP: regression coefficient estimate=-0.015, P<0.0001; DBP: regression coefficient estimate=-0.028, P<0.0001). Multiple logistic regression showed that calcium intake was negatively associated with the probability of hypertension (odds ratio (OR)=0.81, 95% confidence interval (CI): 0.74-0.87, P<0.0001). In stratified analysis, calcium intake in youngest adults (age 20-44 years) had the lowest likelihood of hypertension (OR=0.77, 95% CI: 0.64-0.93, P<0.0001), the inverse relationship between calcium intake and probability of hypertension was stronger among females (OR: 0.68, 95% CI: 0.55-0.84, P<0.0001), when compared with the whole sample including all of 14,408 obese adults. The protective effect of calcium intake and hypertension was found significantly in obese non-diabetic adults (OR: OR=0.77, 95% CI: 0.67-0.89, P<0.0001) not in obese diabetic adults. SBP, DBP and calcium intake were log transformed for both ordinary linear regression analysis and logistic regression analysis. Our study findings underscore the need to explore the physiological mechanism between calcium intake and hypertension. In this study, increased calcium intake was associated with the lowest risk of hypertension. Future studies utilizing longitudinal research designs are needed to quantify therapeutic levels of calcium for control of hypertension among obese adults. Increasing calcium intake among American adults may offer promise as a cost-effective strategy to improve hypertension among obese adults; however, further scientific exploration is warranted.

Family-based association analysis of the MAPT gene in Parkinson disease.

The MAPT gene has been shown to be associated with several neurodegenerative disorders, including forms of parkinsonism and Parkinson disease (PD), but the results reveal population differences. We investigated the association of 10 single-nucleotide polymorphisms (SNPs) in the region of MAPT on chromosome 17q21 with PD and age at onset, by using 443 discordant sib pairs in PD from a public dataset (Mayo-Perlegen LEAPS Collaboration). Association with PD was assessed by the FBAT using generalized estimating equations (FBAT-GEE), while the association with age at onset as a quantitative trait was evaluated using the FBAT-logrank statistic. Five SNPs were significantly associated with PD (P < 0.05) in an additive model, and 9 SNPs were associated with PD (P < 0.05) in dominant and recessive models. Interestingly, 8 PD-associated SNPs were also associated with age at onset of PD (P < 0.05) in dominant and recessive models. The SNP most significantly associated with PD and age at onset was rs17649641 (P = 0.015 and 0.021, respectively). Two-SNP haplotypes inferred from rs17563965 and rs17649641 also showed association with PD (P = 0.018) and age at onset (P = 0.026). These results provide further support for the role of MAPT in development of PD.

Study on cement mortar and concrete made with sewage sludge ash.

This study investigated the feasibility of reusing wastewater sludge ash in construction materials to replace partial materials. Wastewater sludge sampled from thermal power plant was burned into sludge ash at 800°C in the laboratory. The sludge incineration ash has low heavy metal including Pb, Cd, Cr and Cu, so it belongs to general enterprise waste. The chemical composition of sludge incineration ash was summed up in SiO2, CaO, Fe2O3 and MgO. Then the wastewater sludge ash is also found to be a porous material with irregular surface. When the sludge ash was used to replace mortar or concrete cement, its water-adsorption capability will result in the reduction of mortar workability and compressive strength. Cement is being substituted for sludge ash, and 10 percent of sludge ash is more appropriate. Sludge ash is reused to take the place of construction materials and satisfies the requests of standard specification except for higher water absorption.

Comparative proteomic analysis of beta-catenin-mediated malignant progression of esophageal squamous cell carcinoma.

beta-catenin has emerged as a key regulator of Wnt signaling pathway, which plays an important role in the development and progression of various cancers. Its accumulation in nucleus of the esophagus squamous epithelium might be the crucial step for the carcinogenesis of esophageal squamous cell carcinoma (ESCC). To detect the proteins correlated with beta-catenin function, we used the established cell lines of pGen-3-con (Eca109 cells transfected by control vector) and pGen-3-CTNNB1 (Eca109 cells transfected by beta-catenin siRNA) as cell models for further analysis. Two-dimensional gel electrophoresis technology was performed to separate the proteins of pGen-3-con and pGen-3-CTNNB1 cell lines, respectively. The differential protein spots were analyzed by software analysis, subjected to in-gel digestion, and identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Consequently, 13 differentially expressed proteins between the two cell lines were identified, of which 14-3-3sigma, prohibitin, and nm23-H1 were further verified by western blotting and quantitative real-time reverse transcriptase-polymerase chain reaction. Then, the tissue microarray and immunohistochemical analysis were employed to research their relationship in ESCC and their corresponding normal mucosa tissues. The upregulation of prohibitin or the downregulation of 14-3-3sigma and nm23-H1 proteins was significantly associated with the proliferation, invasion depth, and lymph node metastasis of ESCC. There were statistically significant correlations between the expression of beta-catenin and the three proteins. The results presented here might provide potential protein markers to elucidate the mechanism of beta-catenin-mediated biologic characteristics for ESCC.

The utilization of thin film transistor liquid crystal display waste glass as a pozzolanic material.

This investigation elucidates the pozzolanic behavior of waste glass blended cement (WGBC) paste used in thin film transistor liquid crystal displays (TFT-LCD). X-ray diffraction (XRD) results demonstrate that the TFT-LCD waste glass was entirely non-crystalline. The leaching concentrations of the clay and TFT-LCD waste glass all met the current regulatory thresholds of the Taiwan EPA. The pozzolanic strength activity indices of TFT-LCD waste glass at 28 days and 56 days were 89% and 92%, respectively. Accordingly, this material can be regarded as a good pozzolanic material. The amount of TFT-LCD waste glass that is mixed into WGBC pastes affects the strength of the pastes. The strength of the paste clearly declined as the amount of TFT-LCD waste glass increased. XRD patterns indicated that the major difference was the presence of hydrates of calcium silicate (CSH, 2 theta=32.1 degrees), aluminate and aluminosilicate, which was present in WGBC pastes. Portland cement may have increased the alkalinity of the solution and induced the decomposition of the glass phase network. WGBC pastes that contained 40% TFT-LCD waste glass have markedly lower gel/space ratios and exhibit less degree of hydration than ordinary Portland cement (OPC) pastes. The most satisfactory characteristics of the strength were observed when the mixing ratio of the TFT-LCD waste glass was 10%.

Study on the species-specificity of Isospora michaelbakeri by experimental infection.

Isospora michaelbakeri is one of the Isospora species most commonly found in the wild field, which can cause severe infection and mortality in young sparrows. In this study, we selected I. michaelbakeri (Chung Hsing strain) as a pathogen to orally inoculate russet sparrows (Passer rutilans), spotted munia (Lonchura punctulata), canary (Serinus canaria), Java sparrows (Padda oryzivora), chicken (Gallus domesticus), ducks (Anas platyrhynchos) and BALB/c mice. The results indicated that I. michaelbakeri infected only russet sparrows. Infected sparrows displayed lethargy, muscular weakness and fluffy feathers, followed by rapid death. Liver and spleen enlargement was seen in the infected birds. Schizonts were identified in thin smears from the venous blood, enlarged livers and spleens. Histopathological examination revealed schizonts and merozoites from the liver and spleen of infected russet sparrows, but not from other species experimentally inoculated with I. michaelbakeri in the present study.

Gene flow in European beech (Fagus sylvatica L.).

Three relatively isolated stands were used to study gene flow in European beech (Fagus sylvatica L.) in Northern Germany. Nine allozyme loci (Got-B, Idh-A, Lap-A, Mdh-B, Mdh-C, Mnr-A, 6-pgdh-A, Pgi-B and Pgm-A) were utilized for multilocus-genotyping adult trees and seeds. Expected heterozygosity (He) ranged from 0.325 to 0.351 for the three stands. F(ST) revealed that there was small differentiation among stands (mean F(ST) = 0.013). The indirect estimates of gene flow (Nm) based on the mean F(ST) were high and the average Nm was 19.14. External gene flow by pollen ranged from 0.7 to 1.2% inferred from new alleles in seed samples. Moreover, paternity analysis was used to assess effective pollen dispersal by inferring paternity of offspring. The weighted mean distances of pollen dispersal for these three stands were 36.8 and 37.1 m based on simple exclusion procedure and most-likely method, respectively. Two of the trees in one stand had rare allozyme alleles (Lap-A1 and Idh-A4, respectively), which were used to directly measure pollen movement away from those trees. The frequency of the rare Lap and Idh alleles in seeds declines as the distance from the source tree increases. The weighted mean distance of pollen dispersal with rare allele Lap-A1 or Idh-A4 was 26.3 m.

The hydration properties of pastes containing municipal solid waste incinerator fly ash slag.

This study investigated the hydration properties of Type I, Type III and Type V cements, mixed with municipal solid waste incinerator fly ash, to produce slag-blended cement pastes. The setting time of slag-blended cement pastes that contained 40% slag showed significantly retardation the setting time compared to those with a 10% or even a 20% slag replacement. The compressive strength of slag-blended cement paste samples containing 10 and 20% of slag, varied from 95 to 110% that developed by the plain cement pastes at later stages. An increased blend ratio, due to the filling of pores by C-S-H formed during pozzolanic reaction tended to become more pronounced with time. This resulting densification and enhanced later strength was caused by the shifting of the gel pores. It was found that the degree of hydration was slow in early stages, but it increased with increasing curing time. The results indicated that it is feasible to use MSWI fly ash slag to replace up to 20% of the material with three types of ordinary Portland cement.

The hydration characteristics and utilization of slag obtained by the vitrification of MSWI fly ash.

This study investigated the effects of slag composition on the hydration characteristics of slag blended cement (SBC) pastes. Synthetic slag samples were prepared by melting CaO-modified and Al(2)O(3)-modified municipal solid waste incinerator (MSWI) fly ash. MSWI fly ash was mixed with 5% CaO and 5% Al(2)O(3) (by weight), respectively, resulting in two fly ash mixtures. These mixtures were then melted at 1400 degrees C for 30 min to produce two types of slag with different contents, designated at C-slag and A-slag. Both the C-slag and A-slag samples exhibited a pozzolanic activity index higher than the unmodified slag sample. The results show that the synthetic slags all met the Taiwan EPA's current regulatory thresholds. These synthetic slags were then blended with ordinary Portland cement (OPC) at various weight ratios ranging from 10 to 40%. The 28-day strength of the C1 paste was higher than that developed by the OPC paste, suggesting that the C-slag contributed to the earlier strength of the SBC pastes. At curing times beyond 28 days, the strength of the A1 paste samples approached that of the OPC paste samples. It can be seen from this that increasing the amount of calcium and aluminum oxide increases the early strength of SBC. The C-slag blended cement paste samples showed an increase in the number of fine pores with the curing time, showing that the C-slag enhanced the pozzolanic reactions, filling the pores. Also, the incorporation of a 10% addition of C-slag also tended to enhance the degree of hydration of the SBC pastes during the early ages (3-28 days). However, at later ages, no significant difference in degree of hydration between the OPC pastes and the SBC pastes was observed with the 10% C-slag addition. However, the incorporation of A-slag did decreased the degree of hydration. A slag blend ratio of 40% significantly decreased the hydration degree.

Formation of heavy metal species during PVC-containing simulated MSW incineration.

The effect of PVC-derived chlorine on heavy metal emissions in MSW incineration was investigated using a tubular furnace and simulated MSW spiked with PVCs and heavy metals (Cd, Cr, Cu, and Zn). The molar ratio of the chlorine content to that of the heavy metal (Cl/M ratio) was varied from 3-200 as one parameter. The results indicated that the major species found in the fly ash were chlorides of alkaline and alkali-earth metals, whereas those identified in the bottom ash were MgSiO3, SiO2 and some complex aluminates and silicates. The emission of heavy metals and/or their compounds, with extreme and medium volatility, tended to be enhanced within the lower Cl/M range, whereas those with a refractory volatility were likely to be affected within the higher Cl/M range. However, those with an extremely refractory volatility were less affected by an increase of the Cl/M ratio. The variation of speciation and partitioning in MSW combustion as affected by the Cl/M ratio are discussed.

CML66, a broadly immunogenic tumor antigen, elicits a humoral immune response associated with remission of chronic myelogenous leukemia.

This report describes a tumor-associated antigen, termed CML66, initially cloned from a chronic myelogenous leukemia (CML) cDNA expression library. CML66 encodes a 583-aa protein with a molecular mass of 66 kDa and no significant homology to other known genes. CML66 gene is localized to human chromosome 8q23, but the function of this gene is unknown. CML66 is expressed in leukemias and a variety of solid tumor cell lines. When examined by Northern blot, expression in normal tissues was restricted to testis and heart, and no expression was found in hematopoietic tissues. When examined by quantitative reverse transcription-PCR, expression in CML cells was 1.5-fold higher than in normal peripheral blood mononuclear cells. The presence of CML66-specific antibody in patient serum was confirmed by Western blot and the development of high titer IgG antibody specific for CML66 correlated with immune induced remission of CML in a patient who received infusion of normal donor lymphocytes for treatment of relapse. CML66 antibody also was found in sera from 18-38% of patients with lung cancer, melanoma, and prostate cancer. These findings suggest that CML66 may be immunogenic in a wide variety of malignancies and may be a target for antigen-specific immunotherapy.

Specific down-regulation of interleukin-12 signaling through induction of phospho-STAT4 protein degradation.

Interleukin-12 (IL-12) plays a critical role in modulating the function of T lymphocytes and natural killer cells. IL-12 has potent antitumor effects in animal models, mediated primarily by its ability to enhance cytolytic activity and secretion of interferon-gamma (IFN-gamma). Unfortunately, the antitumor effect of IL-12 has not been demonstrated in clinical trials. Repeated administration of IL-12 in humans results in decreasing levels of IFN-gamma secretion. To understand the mechanism underlying this loss of responsiveness, the effect of IL-12 on its own signaling in activated human T cells was examined. These experiments demonstrate that the level of the signal transducer and activator of transcription 4 (STAT4) protein, a critical IL-12 signaling component, is dramatically decreased 24 hours after IL-12 stimulation, whereas levels of STAT4 messenger RNA are not affected. The decrease of STAT4 protein appears to be due to specific degradation of phospho-STAT4, possibly through the proteasome degradation pathway. Decreased levels of STAT4 protein lead to decreased STAT4 DNA-binding activity and reduced proliferation and secretion of IFN-gamma. This down-regulation of STAT4 is specific for IL-12 signaling, presumably owing to the prolonged activation of STAT4 induced by IL-12. IFN-alpha stimulation, which leads to transient phosphorylation of STAT4, does not reduce the level of STAT4 protein. These findings provide new insights into the regulation of IL-12 signaling in human T cells, where IL-12 promotes T(H)1 responses, but persistent IL-12 stimulation may also limit this response. The cellular depletion of STAT4 following prolonged IL-12 stimulation may also explain the loss of responsiveness following the repeated administration of IL-12 in clinical trials. (Blood. 2001;97:3860-3866)

8-Nitroxanthine, an adduct derived from 2'-deoxyguanosine or DNA reaction with nitryl chloride.

Activated phagocytic cells generate reactive nitrogen species, including nitryl chloride and peroxynitrite, for host defense against invading pathogens. It has been proposed that these reactive nitrogen species may cause DNA damage and thus contribute to the multistage carcinogenesis process associated with chronic infections and inflammation. Previous studies showed that peroxynitrite reacted with guanine, 2'-deoxyguanosine, or DNA forming 8-nitroguanine. We herein report formation of 8-nitroxanthine as the major nitration product in reactions of 2'-deoxyguanosine or calf thymus DNA with nitryl chloride produced by mixing nitrite with hypochlorous acid, and 8-nitroguanine was a minor product in these reactions. 8-Nitroxanthine was characterized by its NMR and laser desorption ionization mass spectra and by deamination of 8-nitroguanine. Formation of 8-nitroxanthine was also detected by xanthine reaction with various reactive nitrogen species, including nitryl chloride, peroxynitrite, nitronium tetrafluoroborate, and heated nitric and nitrous acid. The identity of 8-nitroxanthine in nitryl chloride-treated dG and DNA was confirmed by co-injection with synthetic 8-nitroxanthine and by its reduction to 8-aminoxanthine. Levels of 8-nitroxanthine and 8-nitroguanine in these reactions were quantified by reversed-phase HPLC with photodiode array detection. Once formed, 8-nitroxanthine was spontaneously removed from DNA with a half-life of 2 h at 37 degrees C and pH 7.4. Therefore, 8-nitroxanthine might be an important DNA lesion derived from reactive nitrogen species in vivo.

The effects of FeCl3 on the distribution of the heavy metals Cd, Cu, Cr, and Zn in a simulated multimetal incineration system.

Recognizing that waste-derived chlorine can enhance heavy metal emissions by forming volatile metallic chlorides during municipal solid waste (MSW) combustion, and that in Taiwan, FeCl3-containing sewage sludge may either be landfilled or coincinerated with other MSW, this study thus investigated the effects of FeCl3 on the speciation and partitioning of heavy metals in a multimetal incineration system by using a tubular furnace and FeCl3-spiked simulated wastes. The molar ratio of chlorine content to heavy metal content (referred to as the Cl/ M ratio), ranging from 3 to 200, was used as a parameter to evaluate the effects of chlorine on the movement of heavy metals between the incinerator discharges. Results indicate that speciation and partitioning were related to the affinity between the chlorine and the heavy metals and between chlorine and hydrogen in the combustion system. The effectiveness of increasing the Cl/M ratio to the formation potential of metallic chlorides and on the shift of heavy metals from the bottom ash to the fly ash and/or the flue gases was found to have in increasing order as follows: Zn>Cu>Cr, a phenomenon basically reflecting the volatility of the heavy metals and their chlorides formed during combustion.

The clearance and metabolism of biotin administered intravenously to pigs in tracer and physiologic amounts is much more rapid than previously appreciated.

Understanding of biotin pharmacokinetics and regulation of metabolism is essential for the determination of the biotin requirement for humans. Using Landrace-Cambrough pigs as a model, we initially demonstrated that biotin binding to protein accounts for only a small percentage of the total biotin in plasma. A physiologic amount of [14C]biotin was administered intravenously to three pigs; nine blood samples were collected over 48 h. Plasma concentrations of 14C-labeled metabolites were negligible for the first 2 h after biotin infusion. Disappearance curves of total 14C and of [14C]biotin were similar; both fit a triexponential function consistent with a three-compartment, open model. To characterize the rapid early phase of disappearance more precisely, a physiologic amount of [14C]biotin was administered intravenously to five pigs; eight blood samples were collected over the first hour and 16 total samples over 48 h. Again a triexponential function provided an excellent fit. The mean half-life values (+/- 1 SD) for the three phases were 0.11 +/- 0.07, 1.43 +/- 0.42 and 22 +/- 4 h. The [14C]biotin accumulated primarily in the liver, kidney and muscle. When administered intravenously at tracer doses to three pigs, [3H]biotin exhibited similar early pharmacokinetics; however, substantial quantities of a 3H-labeled metabolite appeared after 1 h. These studies provide evidence that egress of biotin from plasma is more rapid than previously appreciated. The slower second and third phases may represent transport into the cytosol, biotransformation into intermediates and covalent binding to intracellular proteins. Similar pharmacokinetics are likely to be seen in humans.

Omphalocele, colonic atresia, and Hirschsprung's disease: an unusual cluster of malformations in a single patient.

Omphalocele, colonic atresia (CA), and Hirschsprung's disease (HD) are individually rare congenital malformations. An association between CA and HD has been described, but the co-occurrence of all three malformations has not been previously reported. We present an infant born with all three malformations and review the management issues relevant to this case, with an emphasis on the importance of considering co-existent HD in any infant born with CA.

Effects of the type of sintering atmosphere on the chromium leachability of thermal-treated municipal solid waste incinerator fly ash.

The sintering process offers an opportunity to combine detoxification and resource recovery for the treatment of municipal solid waste (MSW) incinerator fly ash. However, the chromium (Cr) in the sintered fly ash becomes more readily leachable with increasing sintering time and temperature, thus posing severe threats to the environment and human health when the sintered ash is recycled or reused. This study investigated the enhanced leachability of fly ash containing Cr, by heating the chromium (III) oxide (Cr2O3)-spiked fly ash to 800 degrees C in atmospheres containing air, nitrogen gas (N2), and 5% H2 + 95% N2, respectively. The results indicated that trivalent chromium was converted to its soluble hexavalent form during sintering in the air atmosphere; whereas sintering in a nitrogen atmosphere significantly reduced the leachability of Cr due to lack of oxygen (O2) to oxidize. The effects of the sintering temperature on the total chromium content and the leaching concentration in the toxicity characteristic leaching procedure (TCLP) extract are also discussed.