A method for the simultaneous recording of magnetic resonance data relating to an examination subject from at least two different slices by a magnetic resonance sequence, wherein an excitation period of the magnetic resonance sequence that includes at least one sub-section that acts on only one of the slices, and that contains at least one high frequency pulse is used, wherein, to correct the main magnetic field inhomogeneities of the first order, for each slice affected by a sub-section, a correction parameter that modifies the gradient pulses that are to be emitted is determined, taking into account at least one main magnetic field map that describes the spatial distribution of the main magnetic field and a slice position of the affected slice and is applied in the emission of gradient pulses for the respective slice in the sub-section.

Magnetic resonance (MR) imaging is a known technique with which images of the inside of an examination subject may be generated, e.g., of a patient in medical imaging. For this purpose, the examination subject is positioned in a magnetic resonance apparatus in a comparatively strong static, homogeneous main magnetic field, also known as the B0-Feld, with field strengths of 0.2 tesla to 7 tesla and more, such that the nuclear spins thereof are orientated along the main magnetic field. To trigger nuclear magnetic resonances, high frequency excitation pulses (also known as RF-pulses) are radiated into the examination subject. The nuclear magnetic resonances that are triggered are measured as what is known as k-space data. On the basis thereof, MR images are reconstructed or spectroscopy data is acquired. For the spatial encoding of the magnetic resonance data, rapidly switched magnetic gradient fields are superimposed on the main magnetic field. The magnetic resonance data that has been recorded is digitalized and stored as complex numerical values in a k-space matrix. From the k-space matrix that is occupied by values, a relevant MR image may be reconstructed, for example, by a multi-dimensional Fourier transform.
The desire for faster and faster magnetic resonance images in the clinical environment is currently leading to a renaissance of methods in which magnetic resonance data from different volume regions of the examination subject, in particular therefore from different slices in a stack of slices, may be recorded simultaneously. These methods may be characterized in that, at least during a part of the measurement, transversal magnetization of at least two slices is used at the same time for the imaging process ("slice-multiplexing"; e.g., known in as simultaneous multi-slice (SMS) imaging). In conventional multi-slice imaging, the signal from at least two slices is recorded consecutively or alternately, that is, completely independent of each other, with an accordingly longer measurement time.
Known methods for this purpose are "Hadamard-coding", methods with simultaneous echo-refocusing, methods with broadband data recording or even methods that use parallel imaging in the slice direction. The latter methods also include, for example, the blipped Controlled Aliasing in Parallel Imaging (CAIPI) technique, as described by Setsompop et al. in "Blipped-Controlled Aliasing in Parallel Imaging for Simultaneous Multislice Echo Planar Imaging with Reduced g-Factor Penalty", Magnetic Resonance in Medicine 67, 2012, p. 1210-1224.
U.S. Patent Application Publication No. 2016/0313433 A1 and U.S. Patent Application Publication No. 2015/0115958 A1 disclose methods for simultaneous multi-slice measurement.
In such slice-multiplexing methods, what is known as a multiband high frequency pulse is used in order to excite or otherwise manipulate two or a plurality of slices at the same time, for example, to refocus or saturate them. Such a multiband high frequency pulse is, for example, a multiplex of individual single-slice high frequency pulses, which would be used for the manipulation of the slices that are to be manipulated at the same time. In order to be able to separate the resulting magnetic resonance signals from the various slices, each of the individual high frequency pulses is imprinted with a different phase, (e.g., prior to multiplexing), by adding a linear phase shift, for example, as a result of which the slices are shifted with respect to one another in the location domain. Through multiplexing, one obtains, for example, a basic band-modulated multiband high frequency pulse by adding the shapes of the pulses in the individual single-slice high frequency pulses.
As described, for example, in the article by Setsompop et al. cited above, the g-factor-related disadvantages may be reduced by shifts between the slices, by using gradient blips for instance or by modulating the phases of the individual high frequency pulses. As likewise disclosed in the cited article by Setsompop et al., the signals from the slices that have been excited or otherwise manipulated at the same time may first be combined like signals from only one slice in order for them to then be separated in the subsequent processing by a slice GeneRalized Auto-calibrating Partial Parallel Acquisition (GRAPPA) method.
In the prior art, it has also already been suggested in the context of slice-multiplexing to excite or manipulate in a different way different slices that are meant to be scanned at the same time, such that different contrasts emerge. In this context, U.S. Patent Application Publication No. 2017/0108567 A1 proposes a method for simultaneous multi-contrast recording in SMS imaging, in which with "inversion recovery", (IR) images may be acquired at the same time as non-IR images, by applying a single band inversion pulse to only one of the slices.
Likewise, with regard to saturation of certain types of spin, the Larmor frequencies of which differ due to a chemical shift, there are already relevant suggestions in existence. The types of spins possibly considered are spins of fat-bound protons ("fat spins") and spins of water-bound protons ("water spins"). A traditional measure adopted in this context is "fat saturation". In this context, the subsequently published U.S. Patent Application Publication No. 2018/0024214 discloses combining a binomial pulse for water excitation for a slice with a conventional excitation pulse for the other slice in order to acquire one slice with and one slice without fat saturation. The subsequently published U.S. Patent Application Publication No. 2018/0074146 proposes a method of spatial fat-suppression in multi-contrast SMS imaging, in which a pulse sequence acting on only one slice with a binomial pulse for fat excitation and a dephasing gradient are applied upstream of the further high frequency pulses in order to achieve fat saturation in said slice. The problem here is that the fat saturation may be inadequate in regions with strong B0 distortions. This is because, in those regions, the spins experience stronger or weaker dephasing because the gradient moment that is in fact acting on the spins is generated by the combination of the bipolar gradients and of the deviations in the main magnetic field.
Methods based on magnetic resonance, such as tomographic imaging (e.g., magnetic resonance tomography (MRT)) and spectroscopy (e.g., magnetic resonance spectroscopy (MRS)), may need "benign" physical environmental conditions in order to guarantee an optimum quality of the data acquired. For example, this applies to at least one of the criteria including spatial homogeneity, temporal stability, and the absolute accuracy of the magnetic fields relevant to MR methods (B0, the stationary main magnetic field, and B1, the high frequency magnetic field).
Already known methods with which deviations from ideal environmental conditions may be at least partly compensated for include both system-specific adjustments that seek to correct the given parameters of the magnetic resonance apparatus used, such as for example, eddy current-induced dynamic field distortions or likewise gradient sensitivities, and also examination subject-specific adjustments that attempt to compensate for the changes caused by putting the examination subject, (e.g., a patient), into the measurement volume of the magnetic resonance apparatus, such as susceptibility-related static field distortions or spatial variations in the high frequency field, for instance. To compensate for non-ideal environmental conditions, the affected parameters of the magnetic resonance sequences may be adjusted. In particular, parameters that come into consideration here are the respective central excitation frequency (for example, for an improved fat-suppression and/or a reduced EPI image shift), shimming of the B0 field in the first order (for example, for more homogeneous fat-suppression and/or an improved signal-noise ratio (SNR)), a respective electric voltage of each of the high frequency transmission units (for example, for an improved SNR) and/or B1-shimming (for example, for a more homogeneous SNR). Such examination subject-specific parameters may be derived, for example, from B0 field maps or B1 field maps that have been drawn beforehand.
An adjustment of these recording parameters was first described only for coherent volumes and not, for example, for unconnected slices such as those that are excited or manipulated at the same time in slice-multiplexing. Because the slices to be manipulated at the same time in the slice-multiplexing method are normally arranged as far apart from each other as possible in order to make it easier to separate the slices into signals later, with these methods, an optimization volume in which deviations in the environmental conditions may be corrected therefore includes either the entire stack of slices or at least the envelope of the slices that are to be manipulated at the same time. The parameters included therein are therefore only adjusted on average for the optimization volume and may even be randomly unsuitable for the slices that are actually affected. In particular with measurements on regions of the examination subject with spatially rapidly varying environmental conditions, such as in the region of the patient's head, such adjustments of recording parameters averaged out over fairly large volumes may even lead to the result worsening.
The subsequently published German Patent Application Publication No. DE 10 2016 214 088.4, which has been incorporated in its entirety into the disclosure content of the present description, discloses in this context a method for the slice-specific adjustment of RF pulses in recordings of magnetic resonance data relating to an examination subject with the aid of a slice-multiplexing method in which, for each slice that is to be scanned at the same time, single-slice RF pulse parameters are determined on the basis of the slice position, the single-slice RF pulse parameters are corrected on the basis of at least one examination subject-specific parameter map (e.g., B0 map and/or B1 map), which in each case shows the spatial distribution of one system parameter in the examination subject and of the slice position are corrected and a multi-band RF pulse for the manipulation of the slices to be scanned at the same time is generated on the basis of the corrected single-slice RF pulse parameters. Here, parameters to be adjusted relate to the central-excitation frequency, an amplitude-scaling factor (e.g., transmitter voltage) and/or B1 shim parameters. A correction relating to terms of the first order in the main magnetic field is not possible by the high frequency pulses, so that only the aforementioned averaged correction that considers all the slices measured together is suggested there.
This is particularly problematic with regard to different contrasts and the approaches to fat saturation described in the aforementioned because it has transpired that B0 field deviations of the first order are the main reason for a non-homogeneous fat saturation and other inhomogeneous contrasts.

Simultaneous multi-slice recording of magnetic resonance data


The present invention relates to the use of a cytokine-1, preferably from the IL-1 family more preferably IL-1F7b, or an isoform, mutein, fused protein, functional derivative or fragment thereof, capable of binding to IL-18BP or a mutein, fused protein, functional derivative or fragment thereof and capable of inhibiting a receptor of a cytokine-2, cytokine-2 being a member of the IL-1 family, preferably IL-18, in the manufacture of a medicament for the treatment or prevention of a disease which is caused or aggravated by inducing said receptor of cytokine-2.

In 1989, an endotoxin-induced serum activity that induced interferon-γ (IFN-γ) obtained from mouse spleen cells was described (Nakamura et al 1989). This serum activity did not function as a direct inducer of IFN-γ but rather as a co-stimulant together with IL-12, IFN-α/β, TNF or mitogens. An attempt to purify the activity from post-endotoxin mouse serum revealed an apparently homogeneous 50-55 kDa protein (Nakamura et al. 1993). Since other cytokines can act as co-stimulants for IFN-γ production, the failure of neutralizing antibodies to IL-1, IL-4, IL-5, IL-6, or TNF to neutralize the serum activity suggested it was a distinct factor. In 1995, the same scientists demonstrated that the endotoxin-induced co-stimulant for IFN-γ production was present in extracts of livers from mice preconditioned with P. acnes (Okamura at al. 1995). In this model, the hepatic macrophage population (Kupffer cells) expands and in these mice, a low dose of bacterial lipopolysaccharide (LPS), which in non-preconditioned mice is not lethal, becomes lethal. The factor, named IFN-γ-inducing factor (IGIF) and later designated interleukin-18 (IL-18), was purified to homogeneity from 1,200 grams of P. acnes-treated mouse livers. Degenerate oligonucleotides derived from amino acid sequences of purified IL-18 were used to clone a murine IL-18 cDNA (Okamura et al. 1995). Messenger RNAs for IL-18 and interleukin-12 (IL-12) are readily detected in activated macrophages. IL-18 does not induce IFN-γ by itself, but functions primarily as a co-stimulant with mitogens or IL-12. The human cDNA sequence for IL-18 was reported in 1996.
Interleukin IL-18 shares structural features with the IL-1 family of proteins (Nakamura et al. 1993, Okamura et. al 1995, Ushio et al. 1996 and Bazan et al. 1996). Unlike most other cytokines, which exhibit a four-helix bundle structure, IL-18 and IL-1β have an all β-pleated sheet structure (Tsutsui et al. 1996). Similarly to IL-1β, IL-18 is synthesized as a biologically inactive precursor (proIL-18), lacking a signal peptide (Ushio et al 1996). The IL-1β and IL-18 precursors are cleaved by caspase-1 (IL-1β-converting enzyme, or ICE), which cleaves the precursors after an aspartic acid residue in the P1 position. The resulting mature cytokines are readily released from the cell (Ghayur et al. 1997 and Gu et al. 1997).
IL-18 is a co-stimulant for cytokine production (IFN-γ, IL-2 and granulocyte-macrophage colony stimulating factor) by T helper type I (Th1) cells (Kohno et al. 1997) and also a co-stimulant for FAS ligand-mediated cytotoxicity of murine natural killer cell clones (Tsutsui et al. 1996).
Th1 lymphocytes are involved in the immune responses against tumors (Seki et al. 2000). Th1 responses include the secretion of the cytokines IL-2, IL-12, IL-18 and IFN-γ, as well as the generation of specific cytotoxic T lymphocytes recognizing specific tumor antigens. The Th1 response is also a vital arm of host defense against many microorganisms. However, the Th1 response can also be associated with non-desirable effects, such as the development of several autoimmune diseases, inflammation and organ transplant rejection.
Cytokine binding proteins (soluble cytokine receptors) are usually the extracellular ligand binding domains of their respective cell surface cytokine receptors. They are produced either by alternative splicing or by proteolytic cleavage of the cell surface receptor. These soluble receptors have been described in the past: for example, the soluble receptors of IL-6 and IFN-γ (Novick et al. 1989), TNF (Engelmann et al. 1989 and Engelmann et al. 1990), IL-1 and IL-4 (Maliszewski et al. 1990), IFN-α/β (Novick et al. 1994, Novick et al. 1992). One cytokine-binding protein, named osteoprotegerin (OPG, also known as osteoclast inhibitory factor—OCIF), a member of the TNFR/Fas family, appears to be the first example of a soluble receptor that exists only as a secreted protein (Anderson et al. 1997, Simonet et al. 1997, Yasuda et al. 1998).
An interleukin-18 binding protein (IL-18BP) was affinity purified, on an IL-18 column, from urine (Novick et al. 1999). IL-18BP abolishes IL-18 induction of IFN-γ and of IL-8, activation of NF-kB in vitro and induction of IFN-γ in vivo. IL-18BP is a soluble circulating protein, which is constitutively expressed in the spleen, and belongs to the immunoglobulin superfamily. The most abundant IL-18BP isoform, the spliced variant isoform a, exhibits a high affinity for IL-18 with a rapid on-rate and a slow off-rate, and a dissociation constant (Kd) of approximately 400 pM (Kim et al. 1999).
The residues involved in the interaction of IL-18 with IL-18BP have been described through the use of computer modelling (Kim et al. 1999) and based on the interaction of IL-1β with the IL1R type I (Vigers et al. 1997). In the model for IL-18 binding to the IL-18BP, the Glu (E) residue at position 42 and the Lys (K) residue at position 89 of IL-18 have been proposed to bind to Lys-130 and Glu-114 in IL-18BP, respectively (Kim et al. 1999).
IL-18BP is constitutively present in many cells (Puren et al. 1999) and circulates in healthy humans (Urushihara et al. 2000). The high affinity of IL-18BP to IL-18 as well as the high concentration of IL-18BP found in the circulation (20 fold molar excess over IL-18) represents a unique situation in cytokine biology. Therefore, it is presumed that most, if not all, of the IL-18 molecules in the circulation is bound to the IL-18BP. The circulating IL-18BP, which competes with cell surface receptors for IL-18, may act as a natural anti-inflammatory and an immunosuppressive molecule.
Viral agents encode IL-18BP like proteins, for example M. contagiosum viral proteins MC53 and MC54 share a significant homology to mammalian IL-18BP (Novick et al. 1999). M. contagiosum proteins MC53 and MC54 possess the ability to bind and neutralize human IL-18 in a fashion similar to that of IL-18BP (Xiang and Moss 1999). The ectromelia poxvirus p13 protein, which is homologous to IL-18BP, binds human IL-18 and inhibits its activity in vitro. Mice infected with a p13 deletion mutant virus exhibited decreased levels of infectivity (Born et al. 2000). Therefore, infectivity degree seems to correlate with the presence of viral IL-18BP.
The high levels of circulating IL18BP may represent a natural defense against excessive Th1 responses to infection and development of autoimmune diseases.
The cytokines of the IL-1-family, including IL-18, possess a variety of inflammatory and immunoregulatory properties during the first line and secondary response to infection (Dinarello 1996 and Nakanishi 2001). Six new members of the interleukin-1 (IL-1) gene family have been discovered from expressed sequence tag data base searches (Barton 2000, Busfield 2000, Debets 2001, Kumar 2000, Lin 2001, Mulero 1999, Pan 2001 and Smith 2000). These proteins share a common β-barrel pattern consisting of 12.beta.-strands and significant amino acid homology with the IL-1 receptor antagonist (IL-1Ra), IL-1β and IL-18. These new members of the IL-1 family are derived from a common ancestor as are IL-1 and IL-18 (Nicklin 2002, Taylor 2002). Except for IL-18, each maps to the same region on human chromosome 2 (Nicklin 2002, Mulero 2000, Taylor 2002 and Busfield 2000). Their biological function of these IL-1 homologues is presently unknown. Five different splice variants of the novel IL-1 homologue IL-1H4 (IL-IF7a-e) have been described (Busfield 2000, Kumar 2000, Pan 2001, Smith 2000, Taylor 2002). The first isoform described, IL-1F7a, has an unique N-terminus consisting of exon 3 of the IL-1 F7 gene, which is not present in the other splice variants of the gene. The short isoforms IL-IF7c, IL-IF7d and IL-IF7e lack exon 4,2 or both, respectively. Only IL-1F7b and c containing exon 1 and 2 express a N-terminal prodomain that has a potential caspase-1 (ICE) cleavage site(s) (Kumar 2002). In addition to these splice variants, amino acid polymorphisms (V31 G and A42T) exist in IL-1F7b based on two base pair mutations in exon 2 (Kumar 2000, Pan 2001). Despite extensive data base searches and sequencing of the IL-1-gene locus, no murine homologue of IL-1 H4 has yet been found. IL-1F7b shares significant sequence homology with IL-18. The hallmark for IL-18 activity is its ability to induce IFNγ in T-cells or natural killer (NK) cells in the presence of IL-2, IL-12 or IL-15 as costimulant. The activity of IL-18 is mediated via the IL-18R complex consisting of the ligand-binding chain termed IL-18R.alpha. (Torigoe 1997) and a signaling chain termed IL-18β (3 (Born 1998, Kim 2001). Upon binding to the IL-18Rα chain and formation of the hetero complex with the IL-18Rβ chain, IL-18 induces activation of IL-1 receptor-associated kinase and TNF receptor-associated factor 6 (TRAF-6). These activated kinases eventually result in the translocation of nuclear factor .kappa.-B (NF-κB) (Matsumoto, Robinson). IL-1F7b has been reported to bind to the IL-18R.alpha. using a receptor pulldown assay (Pan 2001) or computerchip-based binding studies (BIACORE®) (Mulero 2000). Significant but low affinity binding of Kd=130 mM was only observed for the mature form of IL-1F7b without the propeptide suggesting biological relevance to IL-1F7b processing by ICE (Kumar 2002). Despite the binding to the IL-18Rα, no IL-18-like or antagonistic activity of either pro or mature IL-1F7b was demonstrated (Pan 2001, Kumar 2002).
It has been suggested that interleukin IL-18 is involved in the progression of pathogenicity in chronic inflammatory diseases, including endotoxin shock, hepatitis, and autoimmune-diabetes (Kahiwamura and Okamura, 1998). A further indication of a possible role of IL-18 in the development of liver injury resulted from experiments published by Tsuij et al. (Tsuij et al., 1999), showing an elevated level of IL-18 in lipopolysaccharide-induced acute liver injury in a mouse model. However, the mechanism of the multi-functional factor IL-18 in the development of liver injury has not been elucidated so far.
Liver damage or injury may have diverse causes. It may be due to viral or bacterial infections, alcohol abuse, immunological disorders, or cancer, for example.
Viral hepatitis, due to Hepatitis B virus and Hepatitis C virus, for example, are poorly managed diseases that afflict large number of people world-wide. The number of known hepatitis viruses known is constantly increasing. Apart from Hepatitis B and C virus, at least four other viruses causing virus-associated hepatitis have been discovered so far, called Hepatitis A, D, E and G-Virus.
Alcoholic liver disease is another widespread disease associated with chronic consumption of alcohol. Immune hepatitis is a rare autoimmune disease that is poorly managed. Liver injury also includes damages of the bile ducts. Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by destruction of the intrahepatic bile ducts.
Several studies have demonstrated that damage to the liver in diseases such as alcoholic hepatitis, liver cirrhosis, viral hepatitis and primary biliary cirrhosis is associated with T-helper cell-1 (Th1) responses. In one study, a novel liver injury model was established in mice by targeting of ovalbumin-containing liposomes into the liver, followed by adoptive transfer of ovalbumin-specific Th1 cells. Combined treatment of mice with ovalbumin-containing liposomes and Th1 cell transfer caused an increase in serum transaminase activity that was paralleled with an elevation of serum IFN-γ levels. In sharp contrast, ovalbumin-specific Th2 cell transfer resulted in an increase of serum IL-4 levels but did not induce liver injury. The liver injury was blocked by anti-IFN-γ antibodies and anti-tumor necrosis factor (TNF)-α antibodies. These findings indicate that Th1 cells are the major effector cells in acute liver injury (Nishimura and Ohta, 1999) In another set of studies it was shown that mice over-expressing IFN-γ exhibit spontaneous hepatitis without any pathogen or any other stimulant (Okamoto et al., 1998).
Another study implicated Th1 responses in primary biliary cirrhosis (PBC). PBC is an autoimmune liver disease characterized by destruction of the intrahepatic bile ducts. It is generally believed that cellular immune mechanisms, particularly involving T cells, result in this bile duct damage. The relative strength of Th1 and Th2 responses has recently been proposed to be an important factor in the pathophysiology of various autoimmune diseases. In this study, the subset balance in PBC was evaluated by detection of cytokines specific to the two T-cell subsets, i.e., IFN-γ for Th1 cells and IL-4 for Th2 cells. IFN-γ and IL-4 messenger RNA (mRNA) positive cells were counted in liver sections from 18 patients with PBC and 35 disease controls including chronic active hepatitis C, extrahepatic biliary obstruction, and normal liver, using nonisotopic in situ hybridization and immunohistochemistry. Mononuclear cells expressing IFN-γ and IL-4 mRNA were aggregated in inflamed portal tracts in PBC livers, but were rarely present in extrahepatic biliary obstruction, alcoholic fibrosis, or normal liver sections. The IFN-γ and IL-4 mRNA positive cells in PBC livers were detected in significantly higher numbers than in control livers (P<0,01). Moreover, IFN-γ mRNA expression was more commonly detected than IL-4 expression in PBC livers, and the levels of IFN-γ mRNA expression were highly correlated with the degree of portal inflammatory activity. IFN-γ mRNA-positive cells were detected primarily around damaged bile ducts that were surrounded by lymphoid aggregates. The data indicate that Th1 cells are the more prominent T-cell subset in the lymphoid infiltrates in PBC (Harada et al., 1997).
The cytokine pattern on viral antigen recognition is also believed to exert a profound influence on the resolution of viral infections and viral clearance. One study investigated whether a cytokine imbalance oriented toward Th2 type response plays a role in chronic hepatitis B. Cytokine profiles of peripheral blood mononuclear cells associated with chronic hepatitis B were analyzed by RT-PCR. Upon hepatitis B surface antigen (HbsAg) stimulation, expression of IFN-γ, IL-2, IL-4, and IL-10 was detected in 41%, 8%, 41%, and 50% of the patients, respectively. Among these cytokines, the expression of the Th1 cytokine IFN-γ was associated with high levels of serum AST/ALT (Aspartate aminotransferase/Alanine aminotransferase), representing typical markers of liver damage. Th2 type cytokines were not shown to exert a protective effect on hepatocytes. In conclusion, production of a Th1 cytokine, IFN-γ, by HBsAg-reactive cells was associated with hepatocyte damage in chronic hepatitis B (Lee et al., 1999). High levels of the FAS ligand and its receptor (CD95) were reported in liver of hepatitis B patients (Luo et al., 1997). FAS ligand is considered to be one of the major cytotoxic agents leading to hepatocyte apoptosis.
Another study identified factors associated with the progression of liver injury in 30 hepatitis C virus/RNA (HCV/RNA)-positive untreated patients with chronic hepatitis. Necroinflammatory and architectural damage were evaluated using Ishak's score. Activated hepatic stellate cells (HSC) were visualized by immunohistochemistry for α-smooth muscle actin (αSMA) and quantitated by morphometry. Plasma HCV/RNA was evaluated using a competitive RT-PCR method. To study the type of immune response involved in the progression of liver injury, IFN-γ-positive cells (as expression of a Th1-like response) were evaluated by immunohistochemistry and quantitated by morphometry. It was found that HSC were mostly detected close to areas of lobular necroinflammation or lining fibrotic septa. The αSMA- and Sirius Red-positive parenchyma correlated significantly with necroinflammatory and architectural scores. IFNγ-positive cells were detected in periportal areas associated with the inflammatory infiltrates and significantly correlated with architectural damage. It was therefore concluded that HSC activation and progression of liver injury are associated with a Th1-like response (Baroni et al, 1999). Similarly to the case of Hepatitis B, FAS ligand and its receptor were found in liver and sera of hepatitis C patients (Hiramatsu et al, 1994; Okazaki et al, 1996; Lio et al., 1998)
Th1 cytokines and other Th1 markers were found to be associated with alcoholic hepatitis and liver cirrhosis. Inflammatory stimuli and lipid peroxidation activate nuclear factor κB (NF-κB) and upregulate proinflammatory cytokines and chemokines. In one study, the relationship between pathological liver injury, endotoxemia, lipid peroxidation, and NF-κB activation and imbalance between pro- and anti-inflammatory cytokines was evaluated. Rats (5 per group) were fed ethanol and a diet containing saturated fat, palm oil, corn oil, or fish oil by intragastric infusion. Dextrose isocalorically replaced ethanol in control rats. Pathological analysis was performed and measurements of endotoxin were taken, lipid peroxidation, NF-κB, and messenger RNA (mRNA) levels of proinflammatory cytokines (TNFα, IL-1beta, IFN-γ, and IL-12), C-C chemokines (regulated upon activation, normal T cell expressed and secreted [RANTES], monocyte chemotactic protein [MCP]-1, macrophage inflammatory protein [MIP]-1-α), C—X—C chemokines (cytokine induced neutrophil chemoattractant [CINC], MIP-2, IP-10, and epithelial neutrophil activating protein [ENA]-78), and anti-inflammatory cytokines (IL-10, IL-4, and IL-13). Activation of NF-κB and increased expression of proinflammatory cytokines C—C and C—X—C chemokines was seen in the rats exhibiting necroinflammatory injury (fish oil-ethanol and corn oil-ethanol). These groups also had the highest levels of endotoxin and lipid peroxidation. Levels of IL-10 and IL-4 mRNA were lower in the group exhibiting inflammatory liver injury. Thus, activation of NF-κB occurs in the presence of proinflammatory stimuli and results in increased expression of Th1 proinflammatory cytokines and chemokines (Naji et al., 1999). FAS ligand and its receptor are also elevated in alcoholic liver diseases, suggesting once again that Th1 cytokines are involved in the autoimmune processes induced in alcoholic hepatitis (Galle et al., 1995; Taieb et al, 1998; Fiore et al., 1999).
TNF-α has also emerged as a common pathway in the pathogenesis of alcohol-related hepatic necro-inflammation. Increased levels of hepatic and serum TNF have been documented in animal models of alcoholic liver disease and in human alcoholic liver disease. This dysregulated TNF metabolism has been postulated to play a role in many of the metabolic complications and the liver injury of alcoholic liver disease (Grove et al., 1997; McClain and Cohen, 1989). For instance it was found in one study that patients with alcoholic hepatitis had higher TNF-α levels (mean, 26.3 ng/L; 95% CI, 21.7 to 30.9) than normal subjects (6.4 ng/L; CI, 5.4 to 7.4). Patients who subsequently died had a higher TNF-α level (34.7 ng/L; CI, 27.8 to 41.6) than survivors (16.6 ng/L; CI, 14.0 to 19.2). In patients with alcoholic hepatitis, TNF-α levels correlated positively with serum bilirubin (r=0.74; P=0.0009) and serum creatinine (r=0.81; P=0.0003). Patients with alcoholic hepatitis had higher TNF-α levels than patients with inactive alcoholic cirrhosis (11.1 ng/L; CI, 8.9 to 13.3) and severely alcoholic persons without liver disease (6.4 ng/L; CI, 5.0 to 7.8). Patients with abnormal renal function had lower TNF-α levels (14.1 ng/L; CI, 5.4 to 22.8) than patients with alcoholic hepatitis. It was therefore concluded that elevations in TNF-α in alcoholic hepatitis are most marked in severe cases, suggesting that TNF-α plays a role in the pathogenesis (Bird et al., 1990).
TNF mediates many of the biologic actions of endotoxin. Recent studies have shown that TNF administration may cause liver injury and that TNF may mediate the lethality of the hepatotoxin galactosamine. One of the most potent TNF inducers is endotoxin. Because patients with alcoholic liver disease frequently have endotoxemia and because many of the clinical manifestations of alcoholic hepatitis are known biologic actions of TNF, its activity was evaluated in patients with alcoholic hepatitis. Basal and lipopolysaccharide-stimulated TNF release from peripheral blood monocytes, a major source of TNF production, was determined in 16 patients with alcoholic hepatitis and 16 healthy volunteers. Eight of 16 alcoholic hepatitis patients and only two of 16 healthy volunteers had detectable spontaneous TNF activity (p less than 0.05). After lipopolysaccharide stimulation, mean monocyte TNF release from alcoholic hepatitis patients was significantly increased to over twice that of healthy controls (25.3+/−3.7 vs. 10.9+/−2.4 units per ml, p less than 0.005). It was therefore concluded that monocytes from alcoholic hepatitis patients have significantly increased spontaneous and lipopolysaccharide-stimulated TNF release compared to monocytes from healthy volunteers (McClain and Cohen, 1989.
Lipopolysaccharide (LPS)-binding protein (LBP) and CD14 play key intermediary roles in the activation of cells by endotoxin. Gut-derived LPS has been postulated to participate in promoting pathological liver injury in alcoholic liver disease. It was demonstrated that rats fed intragastrically with ethanol in oil for 4 weeks had elevated levels of CD14 and LBP in their Kupffer cells and hepatocytes, respectively. Expression of CD14 mRNA was also elevated in nonmyeloid cells. Enhanced LBP and CD14 expression rapidly increases the LPS-induced expression of various pro-inflammatory cytokines and correlates with the presence of pathological liver injury in alcoholic liver injury (Su et al., 1998; Lukkari et al., 1999).
Arthritis is a disease involving joint inflammation. The joints show swelling, stiffness, tenderness, redness or warmth. The symptoms may be accompanied by weight loss, fever or weakness. When these symptoms last for more than two weeks, inflammatory arthritis e.g. rheumatoid arthritis may be the cause. Joint inflammation may also be caused by infection, which can lead to septic arthritis. A very common type of arthritis is degenerative joint disease (osteoarthritis).
The medicaments commonly prescribed for arthritis and related conditions are non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs include aspirin and aspirin-like drugs. They reduce inflammation, which is the cause for joint pain, stiffness and swelling of the joints. However, NSAIDs are unspecific drugs having a number of side effects, involving bleeding of the stomach (Homepage of the Department of Orthopaedics of the University of Washington on Arthritis, Frederick Matsen (Chairman), www.orthop.washington.edu). In addition to NSAIDs, Celebrex™, a cyclooxygenase (COX-2) inhibitor, is used to relieve the signs and symptoms of osteoarthritis and rheumatoid arthritis in adults. It is also indicated for the treatment of patients with familial adenomatous polyposis.
WO 01/00229 describes a combination of tumors necrosis factor (TNF) antagonists and COX-2 inhibitors for the treatment of inflammation.
TNF antagonists are also used for the treatment of arthritis. TNF antagonists are described, for example, in WO 9103553.
Studies indicate that the interleukin IL-18 plays a proinflammatory role in joint metabolism. Olee et al. (1999) showed that IL-18 is produced by articular chondrocytes and induces proinflammatory and catabolic responses. The IL-18 MRNA was induced by IL-1β in chondrocytes. Chondrocytes produced the IL-18 precursor and in response to IL-1 stimulation secreted the mature form of IL-18. Studies on IL-18 effects on chondrocytes further showed that it inhibits TGF-β-induced proliferation and enhances nitric oxide production. IL-18 stimulated the expression of several genes in normal human articular chondrocytes including inducible nitric oxide synthase, inducible cyclooxygenase, IL-6, and stromelysin. Gene expression was associated with the synthesis of the corresponding proteins. Treatment of normal human articular cartilage with IL-18 increased the release of glycosaminoglycans. These finding identified IL-18 as a cytokine that regulates chondrocyte responses and contributes to cartilage degradation.
The localisation of Interleukin-1β-converting enzyme (ICE)/caspase-1 in human osteoarthritic tissues and its role in the maturation of interleukin-1beta and interleukin-18 have been shown by Saha et al. (1999). Saha et al. studied the expression and production of caspase-1 in human normal and osteoarthritic (OA) cartilage and synovium, quantitated the level of ICE in OA chondrocytes, and examined the relationship between the topographic distribution of ICE, interleukin-1β (IL-1β), and IL-18, as well as apoptosis of chondrocytes. The experiments performed in this study indicated that ICE was expressed and synthesised in both human synovial membrane and cartilage, with a significantly greater number of cells staining positive in OA tissue than in normal tissue. ICE production was preferentially located in the superficial and upper intermediate layers of articular cartilage. The production of mature IL-1beta in OA cartilage explants and chondrocytes was completely blocked by treatment with a specific ICE inhibitor, which also markedly diminished the number of IL-18-positive cells. The relationship between active IL-1beta and ICE suggests that ICE may promote OA progression by activating this proinflammatory cytokine, and that IL-18 may play a role in cartilage pathology.
Gracie et al. (1999) suggested a proinflammatory role for IL-18 in rheumatoid arthritis. Gracie et al. detected the IL-18 mRNA and protein within rheumatoid arthritis synovial tissues in significantly higher levels than in osteoarthritis controls. It was also shown that a combination of IL-12 or IL-15 with IL-18 induced the IFN-γ production by synovial tissues in vitro. Furthermore, IL-18 administration of collagen/inclomplete Freund's adjuvant-immunized mice facilitated the development of an erosive, inflammatory arthritis, suggesting that IL-18 may be proinflammatory in vivo.
However, so far, apart from chemical compounds, only the blockade of TNFα and IL-1β by using soluble receptors or monoclonal antibodies have been shown to decrease murine collagen-induced arthritis (CIA, which is a mouse model for rheumatoid arthritis) (Williams et al., 1994), and were therefore suggested as a therapeutic for rheumatoid arthritis.
The term "chronic or idiopathic inflammatory bowel diseases" embraces at least two conditions: Crohn's disease and ulcerative colitis. Both are diseases of the gastrointestinal tract, Crohn's disease most commonly affecting the small bowel. When it also involves the colon, the differential diagnosis from ulcerative colitis (see below) can be a problem.
The chronic inflammation and ulceration in Crohn's disease usually starts with either small-intestinal obstruction or abdominal pain which may mimic acute appendicitis; other presentations can relate to its complications. The course of the disease is chronic, and there may be exacerbations and remissions in spite of therapy. Onset is usually in early adult life, with about half of all cases beginning between the ages of 20 and 30 years and 90% between 10 and 40 years. Slightly more males than females are affected.
Microscopy reflects the gross appearances. Inflammation involvement is discontinuous: it is focal or patchy. Collections of lymphocytes and plasma cells are found mainly in the mucosa and submucosa but usually affecting all layers (transmural inflammation). The classical microscopic feature of Crohn's disease is the presence of granule cells surrounded by a cuff of lymphocytes. The incidence of idiopathic inflammatory bowel diseases shows considerable geographic variation. These diseases have a much higher incidence in northern Europe and the United States than in countries of southern Europe, Africa, South America and Asia, although increasing urbanisation and prosperity is leading to a higher incidence in parts of southern Europe and Japan (General and Systematic Pathology, Churchill Livingstone, 3rd edition 2000, JCE Underwood, Ed.).
In Crohn's disease, clinically there are two main groups, the first comprising patients whose disease goes into lasting remission within three years of onset, the second comprising patients with disease persisting beyond three years.
Whatever the aetiology, there is evidence of persistence and inappropriate T-cell and macrophage activation in Crohn's disease with increased production of pro-inflammatory cytokines, in particular interleukins (IL) 1, 2, 6 and 8, Interferon (IFN)-γ and Tumor Necrosis Factor (TNF) α. Crohn's disease is characterised by sustained (chronic) inflammation accompanied by fibrosis. The process of fibroblastic proliferation and collagen deposition may be mediated by transforming growth factor β, which has certain anti-inflammatory actions, namely fibroblast recruitment, matrix synthesis and down-regulation of inflammatory cells, but it is likely that many other mediators will be implicated.
Ulcerative colitis is a non-specific inflammatory disorder of the large intestine, usually beginning in the rectum and extending proximately to a varying extent. Unlike Crohn's disease, ulcerative colitis is confined to the large intestine.
There is growing evidence to indicate that ulcerative colitis is a consequence of altered autoimmune reactivity but mucosal injury could also result from inappropriate T-cell activation and indirect damage brought about by cytokines, proteases and reactive oxygen metabolites from macrophages and neutrophils. This latter mechanism of damage to the colonic epithelium has been termed "innocent bystander" injury. Evidence in favour of autoimmunity is the presence of self-reactive T-lymphocytes and auto-antibodies directed against colonic epithelial cells and endothelial cells, and anti-neutrophil cytoplasmic auto-antibodies (ANCA). However, ulcerative colitis should not be thought of as an autoimmune disease in which mucosal injury is a direct consequence of an immunological reaction to self-antigens (General and Systematic Pathology, supra).
With regard to the therapy of Crohn's disease, most people are first treated with drugs containing mesalamine, a substance that helps control inflammation. Patients who do not benefit from it or who cannot tolerate it may be put on other mesalamine-containing drugs, generally known as 5-ASA agents. Possible side effects of mesalamine preparations include nausea, vomiting, heartburn, diarrhea, and headache.
Some patients take corticosteroids to control inflammation. These drugs are the most effective for active Crohn's disease, but they can cause serious side effects, including greater susceptibility to infection.
Drugs that suppress the immune system are also used to treat Crohn's disease. Most commonly prescribed are 6-mercaptopurine and a related drug, azathioprine. Immunosuppressive agents work by blocking the immune reaction that contributes to inflammation. These drugs may cause side effects like nausea, vomiting, and diarrhea and may lower a person's resistance to infection. When patients are treated with a combination of corticosteroids and immunosuppressive drugs, the dose of corticosteriods can eventually be lowered. Some studies suggest that immunosuppressive drugs may enhance the effectiveness of corticosteroids.
The U.S. Food and Drug Administration has approved the drug infliximab for the treatment of moderate to severe Crohn's disease that does not respond to standard therapies (mesalamine substances, corticosteroids, immunosuppressive agents) and for the treatment of open, draining fistulas. Infliximab, the first treatment approved specifically for Crohn's disease, is an anti-tumor necrosis factor (TNF) monoclonal antibody. Anti-TNF removes TNF from the bloodstream before it reaches the intestines, thereby preventing inflammation.
Antibiotics are used to treat bacterial overgrowth in the small intestine caused by stricture, fistulas, or prior surgery. For this common problem, the doctor may prescribe one or more of the following antibiotics: ampicillin, sulfonamide, cephalosporin, tetracycline, or metronidazole.
Diarrhea and crampy abdominal pain are often relieved when the inflammation subsides, but additional medication may also be necessary. Several anti-diarrheal agents could be used, including diphenoxylate, loperamide, and codeine. Patients who are dehydrated because of diarrhea are usually treated with fluids and electrolytes.
There remains to be a need for effective therapy for the treatment and/or prevention of inflammatory bowel diseases, in particular Crohn's disease (CD) and ulcerative colitis (UC), which have reduced side effects or are ideally even free of side effects.
Both histological and immunological observations indicate that cell-mediated immunity and T cell activation are key features of CD. Studies from humans and experimental models suggest that, in CD, the local immune response tends to be predominantly Th1 in type (Desreumaux et al, 1997) and that locally released cytokines, such as IFN-γ, IL-1β, and TNF-α, contribute to promote and expand the inflammatory response (Reimund et al, 1996).
The cytokine IL-18 plays an important role in Th1 mediated immune response in collaboration with the cytokine IL-12 by stimulating IFN-γ secretion, enhancing natural killer cell cytotoxicity, and stimulating TH1 cell differentiation (Uschito et al, 1996).
IL-18 acts together with IL-12, IL-2, antigens, mitogens, and possibly further factors, to induce the production of IFN-γ. IL-18 also enhances the production of GM-CSF and IL-2, potentiates anti-CD3 induced T cell proliferation, and increases Fas-mediated killing of natural killer cells. Mature IL-18 is produced from its precursor by the IL-1β converting enzyme (ICE, caspase-1). The IL-18 receptor consists of at least two components, co-operating in ligand binding. High- and low-affinity binding sites for IL-18 were found in murine IL-12 stimulated T cells (Okamoto et al., 1998), suggesting a multiple chain receptor complex. Two receptor subunits have been identified so far, both belonging to the IL-1 receptor family (Okamoto et al., 1999). The signal transduction of IL-18 involves activation of NF-κB (Matsumoto et al, 1997).
Recently, IL-18 has been suggested to have some implication in Inflammatory Bowel Diseases (Pizarro et al, 1999; Monteleone et al, 1999).
Pizarro et al. (1999) characterised the expression and localisation of IL-18 in colonic specimens and isolated mucosal cell populations from patients with Crohn's disease. Using a semiquantitative RT-PCR protocol, IL-18 mRNA transcripts were found to be increased in freshly isolated intestinal epithelial cells and lamina propria mononuclear cells from CD compared with ulcerative colitis and noninflamed control patients. IL-18 mRNA transcripts were more abundant in intestinal epithelial cells compared with lamina propria mononuclear cells. Immunohistochemical analysis of surgically resected colonic tissues localised IL-18 to both lamina propria mononuclear cells (specifically, macrophages and dendritic cells) as well as intestinal epithelial cells. Western blot analysis revealed that an 18,3-kDa band, consistent with both recombinant and mature human IL-18 protein, was found predominantly in CD vs UC intestinal mucosal biopsies; a second band of 24 kDa, consistent with the inactive IL-18 precursor, was detected in non inflamed areas from both CD and UC biopsies and was the sole form found in noninflamed controls.
Monteleone et al. (1999) confirmed these findings. Whole mucosal intestinal tissue and lamina propria mononuclear cells of 12 Crohn's disease and 9 ulcerative colitis patients and 15 non-inflammatory bowel disease controls were tested for IL-18 by semiquantitative RT-PCR and Western blot analysis. Transcripts for IL-18 were found in all samples tested. However, increased IL-18 mRNA accumulation was detected in both mucosal and lamina propria mononuclear cells samples from Crohn's disease in comparison to ulcerative colitis and controls. In Crohn's disease, transcripts for IL-18 were more abundant in the mucosal samples taken from involved areas. An 18-kDa band consistent with mature IL-18 was predominantly found in Crohn's disease mucosal samples. In mucosal samples from non-IBD controls, IL-18 was present as the 24-kDa polypeptide. Consistently, active IL-1beta-converting enzyme (ICE) subunit (p20) was expressed in samples from either CD or UC, whereas, in colonic mucosa from non-IBD controls, ICE was synthesised as precursor (p45) only.
Ohta et al. 2001 showed that the expression of IL-18 was increased in psoriatic lesional skin relative to that in normal skin. Their findings indicate that keratinocyte-derived IL-18 participates in the development of the Th1 response in psoriatic lesions, and that its bioactivity appears to be tightly regulated in cutaneous inflammation.
In several animal models, antibodies that neutralize endogenous IL-18 reduce the severity of disease. Endotoxin lethality is prevented by anti-IL-18. Even in models that are interferon-γ independent, neutralization of IL-18 prolongs survival. Anti-IL-18 also protects the liver against cellular injury induced by toxins or activated T cells. In models of hepatic melanoma metastasis, IL-18 blockade reduces the adherence of malignant cells by preventing IL-18 upregulation of vascular endothelial adhesion-1 molecule expression. IL-18 and IL-12 act synergistically to stimulate I cells and natural killer cells to produce IFN-gamma but neutralization of IL-18 prevents IL-12 induction of IFN-gamma. IL-18, like several cytokines, can be used to enhance host defense against tumors in mice a mechanism that is most of ten IFN-gamma-dependent. Nevertheless, it is the proinflammatory portfolio of IL-18, which likely contributes to enhance host defenses. In models or arthritis, lung injury or inflammatory bowel disease, neutralization of IL-18 reveals the important role of this cytokine in mediating inflammation (Dinarello 2000).
Published data imply that IL-18 may play a phatological role in inflammatory CNS diseases. Neutralization of IL-18 was shown to protect from brain injury (Yatsiv et al. 2002), ischemic injury (Mallat et al. 2002), cardiac dysfunction (Raeburn 2002) and neuritis (Yu et al 2002) in animal models.
However, there is evidence that IL-18 promotes host defense against tumors in mice. For example, in syngeneic mice, murine mammary carcinoma cells expressing murine IL-12 or murine IL-18 were less tumorogenic and formed tumors more slowly than did control non-expressing cells (Coughlin et al. 1998). Antibody neutralization studies revealed that the antitumor effects required IFN-γ. In a study by Tasaki it has been observed protective immunity induced in murine colon carcinoma cells by the expression of interleukin-18. Colon cancer cells transduced with vectors encoding the IL-18 gene could not form subcutaneous tumors when introduced in immunocompetent mice, and became resistant to non-transduced inoculated colon cancer cells. Immunohistochemical analysis revealed that the numbers of blood vessels in colon tumors with cells transduced with IL-18 vectors were markedly reduced. The loss of tumorigenicity of colon IL-18 transduced cells was not observed in immunocompromised mice. Thus, the IL-18 secreted from tumor cells acts as an adjuvant since it stimulates T helper type 1 cells to induce antitumor response (Tasaki et al 2000).
It has been suggested that IFN-α, exerts its anti-inflammatory action in vivo in chronic hepatitis C patients inter alia by induction of IL-18BP (Kaser et al. 2002).
In previous work it was found that compared with healthy individuals, the levels of the IL-18BP are markedly elevated in many diseases such as in sepsis (Novick 2001) in Acute Graft versus Host Disease (Zecchina 2001), in Crohn's disease (Corbaz 2002). However it has been found also that in these patients the levels of IL-18 in the circulation are very high and therefore the levels of IL-18BP present in the circulation may not be sufficient for complete neutralization of IL-18.
Thus, is therefore a need to provide means to treat and/or prevent diseases in which a cytokine from the IL-1 family such as IL-18 is involved in their pathology.

Method of treatment using a cytokine able to bind IL-18BP to inhibit the activity of a second cytokine


A game system includes a management apparatus and a game device. The management apparatus includes an authentication section for obtaining results of authentications using first and second identifiers that should correspond to a user. When the results of the authentications are affirmative, a validity time limit is associated with the first identifier. In addition, the game device includes a confirmatory identifier acquirer for acquiring a confirmatory identifier that should correspond to the user, and an inquiry maker for making an inquiry asking the management apparatus to check whether or not the first identifier conforming to the confirmatory identifier is stored in the management apparatus. The inquiry inquires the management apparatus to check whether or not the validity time limit corresponding to the first identifier is a time after the present time when the first identifier conforming to the confirmatory identifier is stored in the management apparatus. A permitter of the management apparatus permits execution of a service associated with the first identifier used in the inquiry when results of checks by the manager in response to the inquiry are affirmative.

Conventionally, game systems, each including a plurality of game devices and a management apparatus communicably connected to the game devices, have been provided. There is a known type of game system that confirms or authenticates the identity of individual users by using recording media, such as cards, in which unique IDs are recorded, and provides individualized services based on the results of the confirmation or authentication.
Such a type of game system is disclosed, for example, in Patent Document 1. Patent Document 1 discloses a technique for recording a game progress status uniquely given to each person in a recording medium, and for providing a service that enables to start a game on the basis of data retrieved from the recording medium when the person wants to start the game (see claims 8, etc., section [0056], etc., and FIG. 11, etc., of Patent Document 1). Since it is necessary to provide individualized services for different people, the system, of course, relies on the identity of each recording medium.
Patent Document 1: JP-A-2004-248922

Game system and management apparatus having a convenient authentication process for ensuring security


A thermal energy storage and recovery device is disclosed which includes (a) an arrangement having first and second ends, the arrangement is configured for guiding a flow of heat transfer fluid between the first second ends, (b) a heat storage material thermally coupled to the arrangement such that along a physical extension of the arrangement a thermal interaction region is formed for thermally coupling the heat transfer fluid with the heat storage material, (c) a fluid terminal connected to the arrangement via a branch duct of the arrangement, the branch duct is located between the first and second ends, and (d) a control device coupled to the fluid terminal and configured that a flow of fluid through the fluid terminal is controllable such that within the arrangement a spatial temperature profile along at least a portion of the thermal interaction region is adjustable. A method and system are also described.

The production of electric power from various types of alternative energy sources such as for instance wind turbines, solar power plants and wave energy plants is not continuous in time. The production may be dependent on environmental parameters such as for instance wind speed (for wind turbines), sunshine intensity (for solar power plant) and wave height and direction (for wave energy plants).

Modification of a spatial temperature profile along a heat exchanging arrangement of a thermal energy storage and recovery device


While displaying a first user interface that corresponds to a display-on state of an electronic device, the device detects a swipe gesture on a touch-sensitive surface. In response to detecting the swipe gesture: when the swipe gesture is in a first direction, the device replaces display of the first user interface with display of a camera application user interface; when the swipe gesture is in a second direction, the device replaces display of the first user interface with display of a mini application object user interface that is configured to include a plurality of mini application objects; when the swipe gesture is in a third direction, the device displays a first page of a multipage control panel user interface; and when the swipe gesture is in a fourth direction, the device displays a notifications user interface that is configured to display a plurality of notifications.

The use of touch-sensitive surfaces as input devices for computers and other electronic computing devices has increased significantly in recent years. Exemplary touch-sensitive surfaces include touchpads and touch-screen displays. Such surfaces are widely used to manipulate user interface objects on a display.
Exemplary manipulations include accessing controls for controlling device functions and functions of remote devices. But methods for performing these manipulations are cumbersome and inefficient. As the realm of uses of remote devices grows, accessing particular controls and functions grows more time consuming. For example, entering a sequence of inputs to access a control via a drill down menu is time consuming for a user, particularly if the location of the desired control is not known beforehand by the user. Navigating between applications to access device functions is also time consuming.

Devices and methods for accessing prevalent device functions


An information processing apparatus comprising: a plurality of processing units; a plurality of individual monitoring units provided for each of the plurality of processing units, that monitor an operation condition of a corresponding processing unit, and judge whether or not the corresponding processing unit is operating normally, and notify the judgment result for the corresponding processing unit to outside; and an administrative unit connected to the plurality of individual monitoring units, that receives notification from any of the individual monitoring units, and performs troubleshooting processing on a processing unit corresponding to an individual monitoring unit that has made a notification that a corresponding processing unit is not operating normally.

In order to improve the reliability of processing in an information processing apparatus, a technique is generally adopted that involves monitoring for the occurrence of a fault in a processor that executes a program, and performing troubleshooting processing.
As a method for performing such monitoring, a method is used in which a watch dog timer is mounted on the processor which is the object monitoring, for example as in the following method. That is to say, when the watch dog timer detects a time out fault, a fault occurrence is notified to an operating system (hereunder OS). At this time, if the situation is such that the OS cannot deal with the fault, the fault occurrence is notified to a service processor that performs collection of hardware information. Furthermore, as another method, there is also a method in which watch dog timers are respectively provided in a plurality of processors, and when one watch dog timer times out, that watch dog timer performs notification of the fault occurrence to the other processor(s).
However, the watch dog timer mounted on a processor in this manner, is usually one capable of detecting hardware faults, but is not provided with sufficient functions for detecting and gathering information of faults attributable to software. Therefore, as yet another method, a method is proposed in which a separate administrative unit independent of the processor, performs monitoring or fault correction processing of the operation conditions of the processor. As an example of such a method, the processor notifies its own operation conditions at predetermined periods, together with a command for controlling startup, stop, and so forth of the monitoring processing, to the administrative unit. On the other hand, the administrative unit, based on the notified operation conditions and the command, judges whether or not a trouble has occurred in the processor, and when detected that a trouble has occurred, performs troubleshooting processing.
Furthermore, as a related art for monitoring operating condition of a system, there has been proposed a technique in which a monitoring object apparatus, that is connected with a monitoring apparatus via network, monitors itself according to an instruction which is received from the monitoring apparatus. In this technique, the monitoring apparatus sends a command for operating the monitoring object apparatus to terminate or re-start the monitoring processing in advance.
The techniques referenced above are described in, for example, Japanese Laid-open Patent Publication No. 01-116739, No. 01-134637, No. 11-85569, and No. 2004-254088.
Here, recently, information processing apparatuses provided with a plurality of processors are becoming popular. Furthermore, the number of processors in a single information processing apparatus is on the rise. In the case of an information processing apparatus provided with such a plurality of processors, a method is generally adopted in which one administrative unit lumps together the operation conditions of the plurality of processors, and monitors these to judge the presence or absence of a trouble, and performs troubleshooting processing on the processor in which a trouble has occurred.
However, in the case in which there are a large number of processors from the view point of improving processing efficiency, when one administrative unit judges, based on the operation conditions of each of the plurality of processors, the presence or absence of a trouble occurrence in each of the processors, the processing load on the administrative unit becomes large. As a result, an obstacle occurs in the processing of the administrative unit, making it difficult to appropriately perform troubleshooting processing.

Information processing apparatus and method


An internal combustion engine having paired opposed power cylinders, and a lever system interconnecting the pistons of the opposed power cylinders with each other and with a crankshaft. The lever system for each pair of cylinders includes the piston rods of the two pistons, each being pivotally connected at one end to its respective piston and being pivotally connected together at their opposite ends and also to one end of a lever arm. The lever arm is connected intermediate its ends to the crankshaft, and its other end is guided to follow a linear path and acts as a moveable fulcrum for the lever system. A compressor driven in rotation by the crankshaft supplies air to the cylinders.

This invention relates to two-cycle internal combustion engines of the lever type and, more particularly, to improvements to two-cycle internal combustion engines of the kind described in U.S. Pat. No. 3,608,530 issued on Sept. 28, 1971 to one of the present applicants.
In general, two-cycle engines of the lever type have opposed power cylinders and separate air or air-fuel charging cylinders and a lever system interconnecting the power and charging cylinder pistons with each other and with a crank shaft. In the engine described in the patent, the disclosure of which is hereby incorporated herein by reference, a plurality of power cylinders (preferably in multiples of four or eight) are so arranged in pairs that the cylinders of each pair are directly opposed in axially aligned relationship in a horizontal plane; in the eight-cylinder engine, four pairs of opposed cylinders are arranged in parallel side-by-side relationship in a common horizontal plane. A single charging cylinder is provided for each pair of opposed power cylinders and are arranged in parallel side-by-side relationship in a common vertical plane, with the axes of the charging cylinders extending vertically and intercepting the axes of the power cylinders at right angles. The piston rod of each charging cylinder is connected at its lower end to the connected outer ends of the piston rods of the horizontally opposed power cylinders. That is, the inner end of each of the three piston rods is pivotally connected to its respective piston and the outer end of each piston rod is pivotally connected to the corresponding outer ends of the other two piston rods.
The crankshaft of the engine is located above the horizontally opposed power cylinders and below the vertically extending charging cylinders. The piston rod of the charging cylinder is connected, at a point intermediate its ends, to an offset crank pin of the crankshaft, and functions as the operative lever of the lever system. In this arrangement, the inner end of the lever (connected to the piston rod of the charging cylinder) is its fulcrum end; the outer end of the lever (which is connected to the outer ends of the piston rods of the power cylinders) is its effort end; and the intermediate connection between the lever and the crankshaft is the load or work-applying portion of the lever. There is no fixed axis for any part of the lever: the fulcrum moves linearly in a vertical line, reciprocating between upper and lower positions; the load-applying portion rotates in a circular path about the axis of the crankshaft; and the effort end of the lever describes an orbital path. The axial alignment of the opposed power cylinders provides a direct thrust, inertia absorbing cushion in each cylinder of each pair of opposed cylinders so as to free the crankshaft from excess inertial loading and making feasible a stroke-to-bore ratio in the power cylinders as high as approximately 2:1.
While the feature of interposing a lever between the power pistons and the crankshaft is essential to achievement of a 2:1 stroke-to-bore ratio so as to make possible a high torque, low speed engine in a small package, the structure illustrated in the patent has a number of undesirable mechanical features which have not heretofore been successfully overcome. For example, the high profile of the vertically-oriented charging cylinders makes the engine relatively large, and the friction of the charging pistons, which are connected to the moveable fulcrum, placed an undesirably heavy load on the crankshaft, with resulting decrease in engine efficiency. The vertical orientation of the charging cylinders, together with their position above the crankshaft, makes it difficult to properly lubricate the charging cylinder pistons.
Also, due to the orientation of the charging cylinders relative to the power cylinders, the outer end of the piston rod of each of the opposed power cylinders and also the outer end of the piston rod of the associated charging cylinder are pivotably connected along the common axis of a connecting pin passing through aligned holes near the ends of each of the three piston rods, with the result that their other ends (i.e., the end connected to a piston) do not lie in the vertical plane defined by the central axes of the three cylinders. As a consequence, at least two the piston rods are necessarily bent along some portion of their length, thus requiring that forces other than compression and tension must be taken into account in the design of the piston rods.
A primary object of the present invention is to provide an improved lever-type engine which avoids the above-outlined undesirable features of the engine described in the aforementioned patent.
Another object of the invention is to provide a lever-type engine of the character described, wherein opposed power cylinders are axially aligned to provide a direct thrust and are supplied with air from a compressor driven in rotation by the crankshaft, thereby to eliminate the troublesome charging cylinders of the prior art engine.
Another object is to provide a lever-type engine of the character described, wherein the power cylinders are arranged in a horizontal plane disposed above the crankshaft and which takes advantage of the slidable fulcrum principle with a simple, relatively short connecting linkage between the power pistons and the crankshaft.

Lever-type two-cycle internal combustion engine


The instant disclosure relates to a fluorine-containing ethylene-vinyl alcohol copolymer (EVOH) resin composition as well as mixture and blend thereof. The fluorine-containing EVOH resin composition comprises EVOH and fluorine-containing particles, wherein the fluorine-containing EVOH resin composition has a total fluoride ion content ranging from 45 to 41000 ppm. The invention can reduce the adhesion of EVOH to the inside of the extruder, and effectively reduce the appearance of gel or gelled substance in subsequent finished products.

EVOH resins are widely used in laminates for preserving perishable items. For example, EVOH resins and laminates are commonly used by the food packaging industry, medical device and supplies industry, pharmaceutical industry, electronics industry, and agricultural chemicals industry. EVOH resins are often incorporated as a distinct layer within a laminate to serve as an oxygen-barrier layer.
Die build-up often occurs during extruding processes utilizing EVOH. Another common problem with extruding processes utilizing EVOH is undesirable screw sticking. These problems may reduce the visual appearance of films formed from the EVOH as well as the mechanical strength. Moreover, these issues have not be sufficiently addressed or solved with conventional technology.
For example, to removing EVOH adhering to the inside of the machine equipment in the conventional technology is to add boron. However, once the boron ion concentration is too high, it will easily cause the current and pressure of the extruder to increase, and uneven dispersion of boron ions will cause too much gel in the subsequently formed film, resulting in poor film appearance.
Thus, there is a continued need for EVOH resins that provide better film mechanical properties and enable cost effective manufacturing processes.

This patent is subject to a terminal disclaimer.

Fluorine-containing ethylene-vinyl alcohol copolymer resin composition as well as mixture and blend thereof


A new rechargeable lithium battery system is provided that contains no melic lithium; the system including a transition metal sulfide anode, a lithiated transition metal oxide cathode, and a solution of a lithium salt in an aprotic organic solvent as the electrolte.

The class of lithium intercalating transition metal oxides and transition metal sulfides are particularly attractive for battery applications because of their inherently high energy content. However, the known lithium/oxide and lithium/sulfide combinations have lithium anodes that are subject to reaction with the solvent and electrolyte. The reactions result in losses in cell capacity and cycle life. Also, metallic lithium is a very energetic and unstable material that is a possible safety hazard in cells that short circuit or are abused.

The United States of America as represented by the Secretary of the Army


An exhaust manifold for vehicle is disclosed. First and fourth runners among a plurality of runners connected to cylinders of an engine are respectively connected to sides of a gas confluence part. Second and third runners disposed between the first and fourth runners are joined together integrally before being connected to the gas confluence part.

The present invention relates to an exhaust manifold for a vehicle and, more particularly, to an exhaust manifold uniformly distributing exhaust gas passing through the catalytic converter and preventing formation of cracks due to thermal stress.
Generally, the exhaust manifold is the part which collects the exhaust gasses from the respective cylinders of the engine to lead the flow of the collected exhaust gas to an exhaust pipe. In a 4-cylinder engine, usually four runners or pipes are used. In one type, the four runners are directly connected to a gas confluence part that is connected to the catalytic converter and leads to the exhaust pipe and muffler. In another type, the runners are connected in two pairs respectively to the gas confluence part.
The former type (in which the four runners are directly connected) is generally called 4-1 type. In this type first, second, third and fourth runners are connected to a gas confluence part with uniform spacing between the runners at the point they join the confluence part. The gas confluence part is provided with a sensor installation slot for installing an oxygen sensor.
While this type of manifold has a simple structure, the spacing between the runners is narrow where it joins the gas confluence part. As a result, the gas confluence part frequently cracks due to thermal stress, with the result that the overall life of such an exhaust manifold is decreased. An additional drawback exists in that exhaust gas interferences occur between the runners in accordance with the ignition sequence (first cylinderxe2x86x92third cylinderxe2x86x92fourth cylinderxe2x86x92second cylinder).
The second type of manifold (in which the four runners are connected to the gas confluence part in two pairs) is generally called 4-2-1 type. In this type the first and fourth runners are joined together in a Y-shape before being connected to the gas confluence part. Likewise, the second and third runners are joined together in a Y-shape before also being connected to the gas confluence part. As a result, only two passages, i.e., a passage which has been formed by the joining of the first and fourth runners, and another passage which has been formed by the joining of the second and third runners, are connected to the gas confluence part. The gas confluence part is also provided with a sensor installation slot for installing an oxygen sensor.
This 4-2-1 type exhaust manifold has an advantage that the flow of the exhaust gas is more efficient compared with the 4-1 type exhaust manifold. However, in this exhaust manifold, because the first runner and the fourth runner face toward each other, if the length of the first and fourth runners is too short, an exhaust gas interference cannot be avoided in accordance with the igniting sequence (first cylinderxe2x86x92third cylinderxe2x86x92fourth cylinderxe2x86x92second cylinder). As with the 4-1 type exhaust manifold, the spacing between the runners is narrow where they join the confluence part, again resulting in thermal stress cracks.
Further, the 4-2-1 type exhaust manifold is more complicated in its structure compared with the 4-1 type exhaust manifold. Consequently, the manufacture is more difficult and the weight greater
In an embodiment of the present invention, first and fourth runners of an exhaust manifold are respectively directly connected to a gas confluence part, while second and third runners are joined together before connecting to the gas confluence part. With this arrangement, flow of exhaust gas is more efficient in streaming to the gas confluence part, and exhaust gas interference is prevented in accordance with the igniting sequence (first cylinderxe2x86x92third cylinderxe2x86x92fourth cylinderxe2x86x92second cylinder). Also, spacing between the runners is widened at the gas confluence part so as to reduce or prevent formation of cracks due to thermal stress.
In a further preferred embodiment of the present invention, the cross sectional area of the runners at the connection point to the confluence part is expanded, whereby the flow velocity of the exhaust gas is slowed to more uniformly distribute exhaust gas passing through the catalytic converter so as to improve its performance.


The axial play of a gearbox shaft (3) that meshes with a gearbox output (7) is determined by measuring the translational travel of the rotationally driven gearbox shaft (3) between the axial end stops (A1; A2) thereof while simultaneously blocking the gearbox output (7). The end stops define the axial play of the gearbox shaft (3). The commutator-dependent ripple of the motor current (IM) pertaining to the commutator motor which drives the gearbox shaft (3) in a drive unit (1; 2) is evaluated as the representative variable for the translational travel.

The invention relates to a device and method for detecting the axial play of a gearbox shaft that meshes with a gearbox output, particularly a worm shaft of a gear motor actuator that meshes with a worm gear. Such actuators with a commutator motor and an adjoining worm gear are provided in particular for motor-driven closing systems, e.g. windows or sun roofs in motor vehicles.
Actuators of the aforementioned type, particularly in mass-produced units comprising a motor enclosure and a gear case with a continuous motor/gearbox shaft, exhibit undesirable tolerance-related axial play. This can cause end stop noises of the motor/gearbox shaft at the axial end stops on both sides as the direction of rotation is reversed.
To limit impermissible axial play, it is known, for instance, from EP 0 133 527 B2 to provide a spacer disk, which has a disk thickness that is based on a prior comparison between the actual, measured axial play and the desired axial play. This spacer disk is the contact part for at least one axial end face of the gearbox shaft, which merges into the motor shaft of a motor enclosure of a commutator motor that is flanged to the gear case receiving the gearbox shaft.
An object of the present invention is to detect, with little measurement complexity, the axial play of a gearbox shaft. It is another object to check the accuracy of an adjustment in cases where the gear parts or the motor drive parts have already been mounted in the gear case or the motor enclosure and their axial play has already been adjusted.
These and other objects are attained by a device for detecting the axial play of a gearbox shaft that meshes with a gearbox output, which device includes: means for rotationally driving the gearbox shaft between axial end stops of the gearbox shaft that limit axial play of the gearbox shaft; means for blocking the gearbox output while the gearbox shaft is driven; and means for determining a translational travel of the rotationally driven gearbox shaft between the axial end stops. The objects are also achieved by a method for detecting the axial play of a gearbox shaft that meshes with a gearbox output, the method including: rotationally driving the gearbox shaft between axial end stops of the gearbox shaft that limit the axial play of the gearbox shaft; blocking movement of the gearbox output during said rotational driving of the gearbox shaft; and determining the translational travel of the rotationally driven gearbox shaft. Advantageous embodiments of the invention are the subject of the dependent claims.
Blocking, e.g. locking, the gearbox output when the gear parts or motor parts have already been mounted and the gearbox shaft is already meshing with the gearbox output causes the motor drive to displace the gearbox shaft in a translational movement while it is secured relative to the gearbox output. As a result the actual axial play can be measured and the necessary adjustment determined, or it can be checked to ensure that the adjustment has already been made. For instance, if a spacer disk failed to be inserted due to an error or, if it was inserted, was lost again during the further assembly process, particularly during greasing, this defect can be detected.
The translational travel representing the corresponding axial play can be particularly easily determined by evaluating, in particular counting, the periodicity associated with the segment interruption of the commutator motor, i.e. the pulses of the driving commutator motor current or motor voltage characteristic, which has a corresponding ripple.
Determining the position of a part that is operationally displaced by a worm gear/commutator motor drive unit and is moved translationally or rotationally via the worm shaft and the worm gear meshing therewith by analyzing the commutation-dependent ripple of the motor current is known per se, for instance, from DE 41 38 194 A1.

Device and method for detecting axial play


Disclosed herein are a system and method for producing paint templates for painting a design on a target surface. The system includes a processor configured to generate a geo-file of paint template designs. The processor includes a design module configured to parse the design into a set of paint sub-designs and a template design module configured to generate the geo-file of paint template designs based on the set of paint sub-designs. The generated geo-file of paint template designs includes a paint template design that corresponds to a paint sub-design. The system further includes a plotter configured to produce a set of paint templates based on the geo-file of paint template designs. Each paint template design includes a set of alignment marks and each paint template is produced with a set of alignment apertures corresponding to the set of alignment marks.

Designs and/or logos are painted on target surfaces of many parts or structures. For example, aircraft often include a design or logo painted on a target surface of the fuselage. Some paint designs include multiple layers of paint that blend multiple colors and/or transition from one color to another color.
Multiple paint templates are utilized to apply the multiple layers of paint on a target surface. Generally, a set of ordered paint templates are designed and utilized to facilitate painting the paint design on the target surface. To begin the painting process, an initial paint template is utilized to facilitate applying a first paint layer on the target surface. Subsequent paint templates are then utilized to apply subsequent paint layers over and/or adjacent to one or more previous paint layers. This process continues until painting the design is completed.
Conventional systems and methods for generating a paint template design and/or producing a paint template are performed manually. Manual generation of the paint template design and/or paint template production is a relatively slow and/or costly process. In addition, inconsistencies can arise between two different paint template designs and/or paint templates because of human error and/or the differences between the individual(s) that manually generate the paint template designs and/or paint templates.

Paint design template production and associated systems and methods


An image-receiving sheet for thermal dye-transfer recording using a sublimable dye is disclosed, comprising a support having thereon an image-receiving layer for receiving a transferred image from a coloring material-transferring sheet, wherein said image-receiving layer is a layer formed by coating a substantially solvent-free coating composition comprising (A) a macromonomer dyeable with a sublimable dye and containing a radical polymerizable functional group at one terminal of the molecular chain thereof, said macromonomer being solid at room temperature, dissolved in (B) a liquid radiation-curable monomer and/or oligomer on a support and irradiating the coat with radiation. The image-receiving sheet has high surface gloss, undegoes no blocking with the coloring material-transferring sheet, and provides a recorded image having high density and excellent storage stability.

In recent years, a full color recording system for directly recording an image photographed with a video camera, an image on a TV, a video tape recorder, a video disk, a computer, etc. on a recording material has been extensively developed. In particular, attention has been aroused on a recording system in which a support coated with a coloring material which is melted, evaporated, or sublimated by application of heat is superposed on a recording sheet (image-receiving sheet), and the coloring material is heated with a thermal head according to recording signals and then transferred to the recording sheet to form an image through adhesion, adsorption, or dye-fixing. One of the admitted characteristics of this recording system is that plain paper or a synthetic resin film, etc. may be used as the image-receiving sheet.
However, when plain paper or a resin film is used as the image-receiving sheet, the dye-fixing, in particular, is difficult to accomplish. As a result, not only is the resulting recorded image low in color density, but serious fading occurs with time.
It has been therefore suggested to coat a support of an image-receiving sheet with a thermoplastic resin, e.g., a polyester resin, to form an image-receiving layer. However, since a thermal recording head of a thermal dye-transfer recording device is generally heated to 200.degree. C. or higher, an ink binder in the coloring material-transferring sheet and the thermoplastic resin in the image-receiving layer are softened or melted by heat to cause fusion therebetween. As a result, the both sheets are difficult to peel apart after recording or the ink layer itself of the coloring material-transferring sheet is transferred to the image-receiving sheet (this phenomenon is hereinafter referred to as blocking).
In order to prevent fusion between the coloring material-transferring sheet and the image-receiving sheet, it has been proposed to incorporate a pigment into the resin constituting the image-receiving layer to rough the surface of the image-receiving layer as disclosed in JP-A-57-107885 (the term "JP-A" as used herein means an "unexamined published Japanese Patent Application"); to coat a release agent, e.g., silicone grease, on the image-receiving layer as disclosed in JP-A-59-165688; or to incorporate a release agent, e.g., a silicon compound, into the image-receiving layer as disclosed in JP-A-60-34898, JP-A-60-212394, and JP-A-61-237694.
In the former method using a pigment, however, contact between the coloring material-transferring sheet and the image-receiving sheet at the time of dye transfer is insufficient due to the surface roughness, resulting in reduction of image density or color unevenness. In addition, the dye adhered onto the surface of the pigment tends to stain other materials, such as paper. The latter method using a release agent is also disadvantageous in that the transferred dye is affected by the release agent, causing smearing of the recorded image or reduction of image density.
Other approaches include a method in which a mixture of a thermoplastic resin and a radical polymerizable compound is cured to form an image-receiving layer having improved heat resistance as disclosed in JP-A-58-212994 and a method in which a crosslinked heat-resistant release layer is provided on an image-receiving layer as disclosed in JP-A-62-116189. These methods have turned out, however, only to provide insufficient recording density if the curing or crosslinking is conducted to such a degree enough to prevent blocking.
Moreover, all the above-described methods use a coating composition containing a large amount of an organic solvent or water so that a drying means and a large quantity of energy are required for drying the solvent. In addition, the organic solvent gives rise to environmental, handling, safety and economical problems because of its harmfulness to human bodies, a fear of explosion, and expensiveness.
On the other hand, JP-A-62-173295 recommends a method using a solvent-free coating composition, in which a radical polymerizable oligomer whose cured product has a glass transition temperature of not higher than 65.degree. C. is coated on a support and crosslinked by irradiation. However, an attempt of obtaining high recording density by this method has turned out to give a recorded image which is liable to bleeding or lacks storage stability.

Image-receiving sheet for thermal dye-transfer recording


A system that provides information about media content stored in a storage device coupled to an interactive media services client device. In one embodiment, the system includes a memory with logic, and a processor configured with the logic to provide a symbol that represents the duration of at least one media content instance of a plurality of media content instances stored in the storage device. Preferably, the processor is further configured with the logic to provide a recorded portion in the symbol that represents the portion of the media content instance that is accessible to a user.

The present invention is generally related to television systems, and, more particularly, is related to personal video recording.
With recent advances in digital transmission technology, subscriber television systems are now capable of providing much more than the traditional analog broadcast video. In implementing enhanced programming, the home communication terminal device (xe2x80x9cHCTxe2x80x9d), otherwise known as the set-top box, has become an important computing device for accessing media content services (and media content within those services) and navigating a user through a maze of available services. In addition to supporting traditional analog broadcast video functionality, digital HCTs (or xe2x80x9cDHCTsxe2x80x9d) now also support an increasing number of two-way digital services such as video-on-demand and personal video recording.
Typically, a DHCT is connected to a cable or satellite, or generally, a subscriber television system, and includes hardware and software necessary to provide the functionality of the digital television system at the user""s site. Preferably, some of the software executed by a DHCT is downloaded and/or updated via the subscriber television system. Each DHCT also typically includes a processor, communication components, and memory, and is connected to a television or other display device, such as a personal computer. While many conventional DHCTs are stand-alone devices that are externally connected to a television, a DHCT and/or its functionality may be integrated into a television or personal computer or even an audio device such as a programmable radio, as will be appreciated by those of ordinary skill in the art.
DHCTs are typically capable of providing users with a very large number and variety of media content choices. As the number of available media content choices increases, viewing conflicts arise whereby the user must choose between watching two or more media content instances (e.g. discrete, individual instances of media content such as, for a non-limiting example, a particular television show or xe2x80x9cprogramxe2x80x9d), all of which the user would like to view. Further, because of the large number of viewing choices, the user may miss viewing opportunities. Buffering of media content instances in memory, or more recently, in storage devices (e.g. hard disk drives) coupled to the DHCT, has provided some relief from the conflict in viewing choices while providing personal video recording functionality. However, current buffering mechanisms for personal video recording are confusing to the user. Therefore, there exists a need to make personal video recording easier for users to understand.
Thus, a heretofore unaddressed need exists in the industry to address the aforementioned deficiencies and inadequacies.

Program position user interface for personal video recording time shift buffer