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Severe liver abscess infections caused by hypervirulent clonal-group CG23 Klebsiella pneumoniae have been increasingly reported since the mid-1980s. Strains typically possess several virulence factors including an integrative, conjugative element ICEKp encoding the siderophore yersiniabactin and genotoxin colibactin. Here we investigate CG23's evolutionary history, showing several deep-branching sublineages associated with distinct ICEKp acquisitions. Over 80% of liver abscess isolates belong to sublineage CG23-I, which emerged in ~1928 following acquisition of ICEKp10 (encoding yersiniabactin and colibactin), and then disseminated globally within the human population. CG23-I's distinguishing feature is the colibactin synthesis locus, which reportedly promotes gut colonisation and metastatic infection in murine models. These data show circulation of CG23 K. pneumoniae decades before the liver abscess epidemic was first recognised, and provide a framework for future epidemiological and experimental studies of hypervirulent K. pneumoniae. To support such studies we present an open access, completely sequenced CG23-I human liver abscess isolate, SGH10.

The use of dissolved hydrogen as an early warning signal of digester failure and a control parameter to operate anaerobic digesters was investigated. A sensitive, on-line method was developed for measuring trace levels of dissolved hydrogen in a semi-permeable membrane, situated within the biomass of a 1 L laboratory anaerobic digester, using trace reduction gas analysis. At normal operating conditions, the dissolved hydrogen partial pressure (2 to 8 Pa) was found to be linearly correlated with the loading rate of the digester, and was a sensitive indicator of the effect of shockloads as well as gradual overloading. An increase in hydrogen partial pressure above a critical concentration of 6.5-7 Pa indicated the initial stage of digester overloading (i.e., volatile fatty acids accumulation). A H2-based computer control system, using a critical hydrogen partial pressure of 6.5 Pa as the setpoint, was found to be effective for the safe operation of a laboratory digester close to its maximum sustainable loading rate. The existence of a relationship between hydrogen level and organic loading rate was also confirmed on a 600 m3 industrial digester, with digester overloading occurring at hydrogen concentrations above 7 Pa. The results suggest that the dissolved hydrogen concentration is capable of being a sensitive on-line parameter for the automated management of anaerobic digesters near their maximum sustainable loading capacity. The use of dissolved hydrogen as an early warning signal of digester failure and a control parameter to operate anaerobic digesters was investigated. A sensitive, on-line method was developed for measuring trace levels of dissolved hydrogen in a semi-permeable membrane, situated within the biomass of a 1 L laboratory anaerobic digester, using trace reduction gas analysis. At normal operating conditions, the dissolved hydrogen partial pressure (2 to 8 Pa) was found to be linearly correlated with the loading rate of the digester, and was a sensit

For modeling of biological processes that operate close to the dynamic equilibrium leg (eg. anaerobic processes), it is critical to prevent the prediction of positive reaction rates when the reaction has already reached dynamic equilibrium. Traditional Michaelis-Menten based models were found to violate the laws of thermodynamics as they predicted positive reaction rates for reactions that were endergonic due to high endproduct concentrations. The inclusion of empirical 'product inhibition factors' as suggested by previous work could not prevent this problem. This paper compares the predictions of the Michaelis-Menten Model (with and without product inhibition factors) and the Equilibrium Based Model (which has a thermodynamic term intoduced into its rate equation) with experimental results of reactions in anaerobic bacterial environments. In contrast to the Michaelis-Menten based models that used traditional inhibition factors, the Equilibrium Based Model correctly predicted the nature and the degree of inhibition due to endproduct accumulation. Moreover, this model also correctly predicted when reaction rates must be zero due to the free energy change of the conversion reaction being zero. With these added advantages, the Equilibrium Based Model thus seemed to provide a scientifically correct and more realistic basis for a variety of models that describe anaerobic biosystems. For modeling of biological processes that operate close to the dynamic equilibrium (eg. anaerobic processes), it is critical to prevent the prediction of positive reaction rates when the reaction has already reached dynamic equilibrium. Traditional Michaelis-Menten based models were found to violate the laws of thermodynamics as they predicted positive reaction rates for reactions that were endergonic due to high endproduct concentrations. The inclusion of empirical `product inhibition factors' as suggested by previous work could not prevent this problem. This paper compares the predictions o

The classical Michaelis-Menten model is widely used as the basis for modeling of a number of biological systems. As the model does not consider the inhibitory effect of endproducts that accumulate in virtually all bioprocesses, it is often modified to prevent the overestimation of reaction rates when products have accumulated. Traditional approaches of model modification use the inclusion of irreversible, competitive, and noncompetitive inhibition factors. This article demonstrates that these inhibition factors are insufficient to predict product inhibition of reactions that are close the dynamic equilibrium. All models investigated were found to violate thermodynamic laws as they predicted positive reaction rates for reactions that were endergonic due to high endproduct concentrations. For modeling of biological processes that operate close to the dynamic equilibrium (e.g., anaerobic processes, it is critical to prevent the prediction of positive reaction rates when the reaction has already reached the dynamic equilibrium. This can be achieved by using a reversible kinetic model. However, the major drawback of the reversible kinetic model is the large number of empirical parameters it requires. These parameters are difficult to determine and prone to experimental error. For this reason, the reversible model is not practical in the modeling of biological processes. This article uses the fundamentals of steady-state kinetics and thermodynamics to establish an equation for the reversible kinetic model that is of practical use in bioprocess modeling. The behavior of this equilibrium- based model is compared with Michaelis-Menten-based models that use traditional inhibition factors. The equilibrium-based model did not require any empirical inhibition factor to correctly predict when reaction rates must be zero due to the free energy change being zero. For highly exergonic reactions, the equilibrium-based model did not deviate significantly from the Michaelis-Menten mode

The liver plays an important role in glucose homeostasis. PET studies with 2-[F-18]fluoro-2-deoxy-D-glucose (FDG) of the liver (e.g., in neoplasms) require an understanding of the effects of dietary conditions on hepatic FDG uptake. METHODS: Twenty studies were performed on 10 normal volunteers (ages 24 +/- 4) after fasting 4 to 19 hr and again after oral consumption of 100 g of dextrose to investigate tracer kinetic model configurations of FDG in the normal liver and to evaluate the impact of oral glucose on liver in normal subjects. Dynamic PET images were acquired for about 1 hr using a Siemens/CTI 931 tomograph. RESULTS: A three-compartment model with an input function delay time parameter was the statistically preferred model configuration. The model estimated transport rate constant from plasma to liver, K1, increased significantly (p < 0.05) from 0.864 +/- 0.136 ml/min/g in fasting studies to 1.058 +/- 0.269 ml/min/g in postglucose studies. Glucose loading also significantly increased (p < 0.01) the rate constant for FDG phosphorylation, k3, from 0.005 +/- 0.003 min-1 in fasting studies to 0.013 +/- 0.007 min-1 in postglucose administration and, consequently, significantly increased both the phosphorylation fraction (k3/(k2 + k3)) and the influx constant (K1k3/(k2 + k3)). No significant differences in the liver-to-plasma transport rate constant, k2, dephosphorylation constant, k4, or distribution volume of FDG (K1/(k2 + k3)) were observed. CONCLUSION: Dynamic FDG-PET studies can be used to evaluate kinetics of liver glucose metabolism. The results indicate that dietary conditions have a significant effect on hepatic FDG kinetics. Because of the higher net FDG uptake by normal liver after glucose loading, fasting conditions are preferred for FDG liver tumor studies to increase the tumor-to-background contrast.

We evaluated the bone metabolic activity in patients with renal osteodystrophy using positron emission tomography and [18F]fluoride ion. Eight patients had secondary hyperparathyroidism (HPT), and three had low-turnover bone disease. Eleven normal subjects were also studied, and three of the eight HPT patients were reevaluated after therapy. A rate constant (K) describing the net transport of [18F] fluoride ion into a bound compartment in bone was calculated using both a three-compartment model and Patlak graphical analysis. Values of K were compared with biochemical data and with histomorphometric indices. The results indicate that K is significantly higher (P < 0.01) in HPT patients than in normal subjects and patients with low-turnover bone disease. Values of K correlated with serum alkaline phosphatase (r = 0.81) and PTH (r = 0.93) levels and with histomorphometric indices of bone formation rate (r = 0.84, P < 0.01) and eroded perimeter (r = 0.77, P < 0.05). Values of K decreased by 40 and 30%, respectively, in two patients who underwent parathyroidectomy and medical therapy. Positron emission tomography studies of bone using [18F]fluoride ion can differentiate low turnover from high turnover lesions of renal osteodystrophy and provide quantitative estimates of bone cell activity that correlate with histomorphometric data., We evaluated the bone metabolic activity in patients with renal osteodystrophy using positron emission tomography and [18F]fluoride ion. Eight patients had secondary hyperparathyroidism (HPT), and three had low-turnover bone disease. Eleven normal subjects were also studied, and three of the eight HPT patients were reevaluated after therapy. A rate constant (K) describing the net transport of [18F] fluoride ion into a bound compartment in bone was calculated using both a three-compartment model and Patlak graphical analysis. Values of K were compared with biochemical data and with histomorphometric indices. The results indicate that K is significantly higher (P < 0.01) in HPT patients than in normal subjects and patients with low-turnover bone disease. Values of K correlated with serum alkaline phosphatase (r = 0.81) and PTH (r = 0.93) levels and with histomorphometric indices of bone formation rate (r = 0.84, P < 0.01) and eroded perimeter (r = 0.77, P < 0.05). Values of K decreased by 40 and 30%, respectively, in two patients who underwent parathyroidectomy and medical therapy. Positron emission tomography studies of bone using [18F]fluoride ion can differentiate low turnover from high turnover lesions of renal osteodystrophy and provide quantitative estimates of bone cell activity that correlate with histomorphometric data. © 1993 by The Endocrine Society.

Imaging and quantifying biochemical and physiological processes with PET clearly has major potential significance for all organ systems and many disease states. Although the full utility and potential of emerging new applications of PET in organs other than the heart and brain must be demonstrated in basic and clinical research studies, the rapidly accumulating aggregate experience in oncology in particular, and in other organ systems and disease states as well, indicates that PET is now truly becoming a modality of both clinical and investigative use for the body as a whole as well as for specific organ systems. Whole-body PET FDG imaging (Fig 9) illustrates the potential of biochemical imaging to map the distribution of cancer throughout the body. With the growing list of radiopharmaceutical and quantitative techniques applicable to cancer studies with PET, this field will continue to realize significant growth.

Positron emission tomography (PET) fluorodeoxyglucose (FDG) studies are useful for identifying foci of increased FDG uptake in liver metastases, because of the high glycolytic rate of malignancies, as well as for monitoring changes in tumor glucose metabolism during treatment. We performed 15 kinetic PET FDG studies in four patients with metastatic liver disease. We produced parametric images of glucose metabolism in terms of the rate constant K (ml/min/g) for net phosphorylation of FDG. Tumor K values, estimated with nonlinear regression, correlated well with K values estimated with Patlak graphical analysis (r = 0.96), validating the assumption of low k4* values in liver metastases and supporting the use of pixel by pixel Patlak plot analysis of the data to generate parametric images. In normal liver, high levels of glucose-6-phosphatase produce much higher values of k4* than in liver metastases. Uncorrected Patlak graphical analysis underestimates K in normal liver, but this further increases the contrast between tumor and liver and facilitates both tumor detection and quantification. The technique is computationally feasible and is well suited for serial evaluations of tumor metabolism during treatment.