AimsTo improve the tolerability and therapeutic application of histone deacetylase inhibitors (HDACi), by application of an esterase‐sensitive motif (ESM), to target pharmacological activity directly to mononuclear myeloid cells expressing the processing enzyme carboxylesterase‐1 (CES1).MethodsThis first‐in‐human study comprised single and multiple ascending dose cohorts to determine safety and tolerability. Pharmacodynamic parameters included acetylation, cytokine inhibition and intracellular concentrations of processed acid metabolite in isolated monocytes. Mechanistic work was conducted in vitro and in a CES1/Es1elo mouse strain.ResultsESM‐HDAC391 showed transient systemic exposure (plasma half‐life of 21–30 min) but selective retention of processed acid for at least 12 hours, resulting in robust targeted mechanistic engagement (increased acetylation in monocytes plus inhibition of ex vivo stimulated cytokine production). ESM‐HDAC391 was well tolerated and clinical toxicities common to non‐targeted HDACi were not observed. ESM‐HDAC391 treatment was accompanied by the novel finding of a dose‐dependent monocyte depletion that was transient and reversible and which plateaued at 0.06 × 109 monocytes/L after repeat dosing with 20 or 40 mg. Characterisation of monocyte depletion in transgenic mice (CES1/Es1elo) suggested that colony stimulating factor 1 receptor loss on circulating cells contributed to ESM‐HDAC‐mediated depletion. Further mechanistic investigations using human monocytes in vitro demonstrated HDACi‐mediated change in myeloid fate through modulation of colony stimulating factor 1 receptor and downstream effects on cell differentiation.ConclusionThese findings demonstrate selective targeting of monocytes in humans using the ESM approach and identify monocytopaenia as a novel outcome of ESM‐HDACi treatment, with implications for potential benefit of these molecules in myeloid‐driven diseases.

Apelin peptides have recently been identified to be the endogenous ligands for the G protein-coupled receptor APJ. However, little is known about the physiological roles of this ligand-receptor pairing. In the present study we investigated the pharmacology of several apelin analogues at the human recombinant APJ receptor using radioligand binding and functional assays. This has led to the identification of key residues in the apelin peptide required for functional potency and binding affinity through structure-activity studies. In particular, we have identified that replacement of leucine in position 5, or arginine in position 2 and 4 of the C -terminal apelin peptide, apelin-13, resulted in significant changes in pharmacology. We also investigated the detailed localization of pre-proapelin and APJ receptor mRNA in a wide range of human, rat and mouse tissues using quantitative RT-PCR, and carried out a detailed immunohistochemical study of the distribution of the APJ receptor in rat brain and spinal cord. Interestingly, the APJ receptor was not only co-localized in white matter with GFAP in the spinal cord, but was also clearly localized on neurones in the brain, suggesting that this receptor and its peptide may be involved in a wide range of biological process yet to be determined.

This paper investigates the solution of manufacturing scheduling problems using different distributed computing schemes. The focus of this paper is on determining the statistically significant effects of a distributed computer model with respect to elapsed solution time and the amount of problem space investigated. Statistical inferences are drawn with respect to the number of processors and how the problem is partitioned. The best combinations of the number of processors and partitioning schemes are presented with respect to problem scenario and size. Additionally, comparisons are made with respect to the performance of different configurations of the distributed computer model.

Two models of posttraumatic stress disorder (PTSD) have received the most empirical support in confirmatory factor analytic studies: King, Leskin, King, and Weathers’ (1998) Emotional Numbing model of reexperiencing, avoidance, emotional numbing and hyperarousal; and Simms, Watson, and Doebbeling's (2002) Dysphoria model of reexperiencing, avoidance, dysphoria and hyperarousal. These models only differ in placement of three PTSD symptoms: sleep problems (D1), irritability (D2), and concentration problems (D3). In the present study, we recruited 252 women victims of domestic violence and tested whether there is empirical support to separate these three PTSD symptoms into a fifth factor, while retaining the Emotional Numbing and Dysphoria models’ remaining four factors. Confirmatory factor analytic findings demonstrated that separating the three symptoms into a separate factor significantly enhanced model fit for the Emotional Numbing and Dysphoria models. These three symptoms may represent a unique latent construct. Implications are discussed.

This paper investigates the solution of manufacturing scheduling problems using different distributed computer schemes. The distributed computer schemes vary with respect to task partitioning, task allocation and the number of processors used. The best combinations of these variations are presented with respect to problem scenario and size. The distributed computing models, are analyzed with respect to computational advantages gained vs. traditional computing models. The models are implemented over a distributed computer network, designed for heterogeneous application, and are transportable to other operating systems and networks of computers. The advantages of these models are discussed and several useful extensions are presented.

A production planning model for an FMS that integrates quality related decisions is presented. A heuristic procedure for resolving the model is presented and performance of the procedure is reported. Initial investigation indicates that the procedure is capable of identifying good solutions expediently. The performance of the procedure is discussed.

In this paper a mathematical programming approach to the configuration of manufacturing planning and control software is presented. A generalized zero-one nonlinear integer programming model is developed for this purpose. The approach is illustrated for the configuration of software that would support activities at the tactical level in a manufacturing environment.

A Tc-99m bone scan of a patient with classic roentgenographic findings of osteopoikilosis revealed multiple foci of increased activity that corresponded to many of the sclerotic foci on the roentgenograms. The authors presume that the abnormal bone scan in this patient reflects active osseous remodeling, similar to what has been observed in bone islands. Previous reports have emphasized the critical role of the radionuclide bone scan for distinguishing osteopoikilosis from osteoblastic bone metastases in patients with a known or suspected primary malignancy. In a young patient, an abnormal bone scan does not exclude the diagnosis of osteopoikilosis if the roentgenographic findings are characteristic of that entity.

A 52-year-old man had an extensive right adrenal pheochromocytoma with invasion of the pararenal inferior vena cava (IVC). Tumor resection required en bloc resection of the infrahepatic IVC. The right kidney was not involved with tumor. Reconstruction of the IVC was performed with an externally supported, expanded polytetrafluoroethylene graft with reimplantation of the right renal veins into the prosthesis. Postoperative patency of the IVC graft and renal veins was confirmed by venacavography and color-flow duplex scanning. This latter technique has been used to document interval patency of the IVC graft 3, 6, and 12 months after surgery.

In addressing planning, design, and control issues of a production system, the solution of a normative model provides answers to planning issues at the aggregate level but fails to capture the time-dependent behavior of the system. This paper illustrates the usefulness of using both mathematical programming and simulation modelling to investigate the material flow characteristics of a “Just in time” system with part quality requirements.

Research in production control which recognizes the strong synergism between product quality and process control is an oft-neglected element of quality engineering. This paper focuses on the optimal control of a sequential production process when product quality is the objective. An algorithm is developed for resolving this problem. The algorithm both identifies the optimal solution and has strong intuitive appeal. To illustrate the procedure, an example is presented for a two-stage discrete part manufacturing system.

This paper focuses on selecting the minimum cost control for a discrete manufacturing system. Information is available to the controller concerning both the process and the status of the incoming part. A Markov programming approach is utilized to explicitly consider the stochastic elements of the process. That is, the part characteristic is assumed to be transformed by the process according to a probability distribution that is unique for each mode of control. Selection of the minimum cost control is performed based on these distributions and information concerning the status of the incoming part. Specifically, the three scenarios assume that the controller is provided with: 1) no information, 2) the distribution of the quality characteristic among the potential values, and 3) complete information about each part. A model for each scenario is developed and an example is presented to further illustrate the concepts. KEY WORDS: Markov programmingmanufacturingdiscrete control.

A mathematical programming approach is presented to relate the impact of operational attributes on part quality in an FMS. A heuristic procedure is presented as a method to find a good feasible solution for this class of nonlinear integer programming problem.

This paper deals with the modelling of a class of discrete-part production control problems that explicitly joins product quality with optimal production control actions. A multistage production system is the basis for modelling, each stage consisting of a processing aspect and a rework/repair aspect. It is assumed that the “quality state” of a part can be measured with certainty at several points within each stage and that control actions can be exercised over each aspect. The state transition function depends on the control action taken and follows a predetermined distribution. Within this general framework, two related problems are studied: (1) independence both stage-to-stage and between states and (2) independence only between states. Both problems can be formulated in a {0, 1} nonlinear mathematical programming format, and numerical examples of each are provided.

Analysis based on Markov chains can be a simple and insightful means of studying a system. In this paper, absorbing and ergodic first-order Markov chains are used to model a simple manufacturing system whose operation and control result in various quality levels. Various ordinary calculations using Markov chains are shown to be helpful in quantifying process and quality characteristics of the system.

The techniques of quality control have been developed over a number of decades, during which the technology of manufacturing was essentially static in terms of control and strategy. Advances within the past decade have led to substantial changes in the manufacturing environment. Changes in the extent, type, and breadth of application of automation call into question some of the basic assumptions of classical quality control. Changes in the mode of manufacturing, such as JIT and emphasis on smaller lot sizes, raise further questions as to the validity of classical quality control in the modern manufacturing environment. This paper addresses some of the questions raised by recent advances in manufacturing and identifies issues for research in quality and process control in the modern manufacturing.

Utilizing microcomputer component compatibility, the optimal microcomputer configuration, capable of performing the desired tasks, may be determined. This paper describes the data file development and the algorithmic process for configuring a specific microcomputer.

This paper discusses how synchronizing finish times for correspondingly numbered process operations of mating component parts (batches) can help a job shop take advantage of some aspects of the just-in-time philosophy.