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Biomedical subjects

Kenji Ikeda

Publications and source records attributed to Kenji Ikeda.

At least 55 records · Page 3Linked to original sources
PubMed2005

Association of amino acid substitution pattern in core protein of hepatitis C virus genotype 1b high viral load and non-virological response to interferon-ribavirin combination therapy.

OBJECTIVE: Patients with high titer (>/=100 kIU/ml) of hepatitis C virus (HCV) genotype 1b do not achieve highly sustained virological response rates to combination therapy with interferon plus ribavirin. Non-virological responders (NVRs, namely ultimate resistant cases) who do not achieve HCV-RNA negativity during treatment are also encountered. We investigated the pretreatment virological features of NVRs. METHODS: We evaluated 50 consecutive Japanese adults with high titer of HCV genotype 1b who received combination therapy for 48 weeks. We investigated the pretreatment substitution patterns in amino acids 1-191 of the core region and amino acids 2209-2248 of NS5A, and early viral kinetics. RESULTS: Overall, a non-virological response was noted in 12 (24%) patients. Multivariate analysis identified serum albumin <3.9 g/dl, substitutions of amino acid 70 in the core region, and substitutions of amino acid 91 as independent and significant factors associated with a non-virological response. Especially, substitutions of arginine (R) by glutamine (Q) at amino acid 70, and/or leucine (L) by methionine (M) at amino acid 91 were significantly more common in NVRs. The falls in HCV-RNA levels during treatment in patients with specific substitutions in the core region were significantly less than in those without such substitutions. CONCLUSIONS: Our results suggest that serum albumin and amino acid substitution patterns in the core region in patients with high titers of HCV genotype 1b may have an effect on combination therapy in NVRs. Further large-scale studies are required to examine the role of amino acid substitutions specific to a non-virological response to combination therapy.

Adult↗
PubMed2005

Usefulness of the serum KL-6 assay in patients with hepatitis C virus.

OBJECTIVE: The aim of this study is to evaluate the serum level of KL-6 in hepatitis C virus (HCV)-positive patients with chronic liver disease. METHODS AND RESULTS: Subjects consisted of 502 HCV-positive patients. The serum samples of these patients stored at -80 degrees C were measured by enzyme-linked immunosorbent assay for KL-6 at the same time. The cutoff point of the serum KL-6 level was defined as 500 U/ml. The serum KL-6 level of the 502 patients ranged between 71 and 2,295 (median, 223) U/ml. Thirty-two of the 502 (6.4%) patients showed an elevated KL-6 level of >500 U/ml. Three of the 32 (9.4%) patients with elevated KL-6 level >500 U/ml had idiopathic pulmonary fibrosis. Multivariate analysis showed that patients achieved elevated KL-6 when: (1) they had hepatocellular carcinoma (HCC; p = 0.0007), and (2) age was >60 years (p = 0.0085). The HCC rate was 37.5% (12/32) in the patients with elevated KL-6 and 8.3% (39/470) in the patients with normal KL-6 group. The median (range) age was 70 (56-77) years in the patients with elevated KL-6 group and 60 (12-92) years in the patients with normal KL-6. CONCLUSION: The patients with HCC aged >60 years had significantly elevated serum levels of KL-6.

Adolescent↗
PubMed2004

Immunolocalization of 14-3-3 isoforms in brains with Pick body disease.

Immunolocalization of 14-3-3 protein isoforms in relation to Pick bodies in Pick body disease (PBD) brains was investigated. Weakly granular immunoreactivity of 14-3-3 proteins was found in neurons in control subjects and in Pick body disease brains. In addition to this granular immunoreactivity, many Pick bodies were immunopositive for 14-3-3 proteins as confirmed with double-immunofluorescence with an anti-PHF tau (AT8) and anti-14-3-3 that recognizes all its isoforms (common). When probed with isoform-specific antibodies, Pick bodies were positive for beta, gamma, epsilon, eta, tau, and zeta isoform and exhibited immunostaining pattern similar to that observed with the anti-14-3-3 proteins (common). In addition, immunoreactivity of sigma isoform, so far considered to be exclusively extraneuronal, was unexpectedly found in Pick bodies, normal hippocampal neurons and brain homogenate from age-matched controls. Although localization of 14-3-3 proteins in Pick bodies suggests their involvement in Pick body formation, their role may be variable dependent on the isoforms differently expressed in different area in the brain.

14-3-3 Proteins↗
PubMed2004

14-3-3 proteins and zeta isoform containing neurofibrillary tangles in patients with Alzheimer's disease.

Immunolocalization of 14-3-3 proteins in Alzheimer's disease (AD) brains was investigated using isoform-specific antibodies. Weak granular immunoreactivity of 14-3-3 proteins was found in neuronal cytoplasm in control subjects and AD brains. Both intracellular and extracellular neurofibrillary tangles (NFTs), as well as neuropil thread-like structures, were immunopositive for 14-3-3 proteins. This was corroborated by triple-fluorolabeling method visualizing paired helical filament (PHF) tau and 14-3-3 epitopes in relation to fibrillary state detected by thiazin red. Pretangle neurons (positive for PHF-tau without fibrillary structure detected by thiazin red) only contained fine granular immunoreactivity (IR) of 14-3-3, which was similarly found in unaffected neurons. Granular cytoplasmic IR of 14-3-3 proteins in pretangle neurons was not colocalized to granular tau-like IR, which suggests that participation of 14-3-3 proteins in NFT formation was restricted to its later stages. Its zeta isoform was most prominent in these NFTs, suggesting that this isoform is a major component involved in the formation of NFTs. In contrast, IR of epsilon isoform was found in the neuropil of the hippocampus and that of sigma isoform was localized to granule cells of the dentate gyrus in AD brains, as seen in the age-matched controls. Expression of 14-3-3 proteins were found to be highly variable and dependent on their isoforms, regions and cell types. Molecular, as well as topographical, dissection of 14-3-3 proteins will provide us with an improved understanding of this molecule in normal and pathological conditions.

14-3-3 Proteins↗
PubMed2004

The distribution of serotonin transporter immunoreactivity in hippocampal formation in monkeys and rats.

To elucidate the anatomical distribution of the serotonergic neurotransmitter system, we identified serotonin transporter (5-HTT) in the hippocampus of rats and monkeys by immunohistochemistry. A widespread and heterogeneous distribution of 5-HTT-immunoreactive fine fibers was noted in the rat brain. However, in monkeys, punctuate 5-HTT-immunoreactive deposits and fewer fibers were observed. The species difference in 5-HTT immunohistochemical staining pattern may be caused by differences in localization of 5-HTT between species.

Animals↗
PubMed2004

Immunohistochemical study of tau accumulation in early stages of Alzheimer-type neurofibrillary lesions.

Accumulation of abnormally phosphorylated tau results in the formation of neurofibrillary tangles (NFTs) in the neuronal cell soma and neuropil threads (NTs) in the cell processes. In the present study, we used immunohistochemistry to investigate serially cut thick tissue sections from the brains of patients with Alzheimer's disease (AD) and non-demented elderly subjects. In the early stages of neurofibrillary pathology, clusters of NTs occurred occasionally in the cerebral cortex. Each NTs cluster, the entire extent of which was observed in the serial sections, corresponded to a dendritic tree that was arborized from a tau-positive neuron. Adult human brain contains six tau isoforms with three having three carboxyl-terminal tandem repeat sequences that are encoded by exon 10 (3R-tau) and the other three having four repeat sequences (4R-tau). Three isoform patterns, 3R-tau(+)/4R-tau(-), 3R-tau(-)/4R-tau(+) and 3R-tau(+)/4R-tau(+), were seen in NFTs in early stage AD lesions. In an individual neuron, the isoform pattern was consistent between the NFTs in the cell soma and the NTs in the cell processes. The results of this study indicate that, in early stages of AD and age-associated neurofibrillary changes, tau accumulates simultaneously in the cell soma and cell processes of affected neurons. The process of AD and age-associated tau pathology is not tau-isoform-specific, but the ratio of 3R-tau and 4R-tau isoforms involved in the neurofibrillary changes varies and is specific to individual neurons.

Aged↗
PubMed2004

Increased expression of neuronal cyclooxygenase-2 in the hippocampus in amyotrophic lateral sclerosis both with and without dementia.

The pathophysiological basis of cognitive dysfunction, including frontotemporal dementia (FTD), in patients with amyotrophic lateral sclerosis (ALS) and ALS with dementia (ALSD) remains unclear. On the other hand, increased expression of cyclooxygenase-2 (COX-2) in the spinal cord is thought to play a pivotal role in motor neuron degeneration in ALS. In this study, to assess the relationship between the neuronal COX-2 expression in the cerebrum, the formation of tau- and alpha-synuclein-negative but ubiquitin-positive neuronal inclusions (UPIs), and dementia in motor neuron disease (MND), we examined neuronal COX-2 immunoreactivity in the frontal cortex and hippocampus of patients with non-demented ALS without UPIs ( n=11), ALSD with UPIs ( n=6), and normal controls ( n=24) using a quantitative immunohistochemical technique. Neuronal COX-2 expression in all CA1-4 in the hippocampus was significantly up-regulated in the ALSD group, and, to lesser degree but significantly, in the ALS group. Neuronal COX-2 expression in the frontal cortex was also significantly up-regulated in the ALSD group but not in the ALS group. These findings suggest that (1) the frontal cortex and hippocampus of MND are involved in the same pathogenic process associated with COX-2 induction that has been observed in spinal anterior horn cells, (2) COX-2 induction in the cerebrum is a pathogenic process that can occur even in the absence of UPI formation in MND, and (3) COX-2 expression in the cerebrum may be associated with cognitive dysfunction in MND.

Aged↗
PubMed2004

Activation of vascular endothelial cells and perivascular cells by systemic inflammation-an immunohistochemical study of postmortem human brain tissues.

We investigated postmortem human brain tissues to determine whether systemic inflammation causes activation of vascular endothelial cells and perivascular cells. In some cases, we used serum concentrations of an acute-phase reactant, C-reactive protein (CRP), as an index of systemic inflammation. Since the serum concentration of CRP at the agonal stage was available only in a limited number of patients, we estimated the degree of systemic inflammation by the intensity of immunohistochemical staining of the residual blood in brain tissue for CRP. Expressions of intercellular adhesion molecule (ICAM)-1, CD40 and cyclooxygenase (COX)-2 were used as markers for activation of vascular endothelial cells. Activation of perivascular cells was estimated by the occurrence of HLA-DR- and CD68-positive perivascular cells. In cases without brain lesions, activation of vascular endothelial cells and perivascular cells was related to the degree of systemic inflammation. In cases with brain lesions, these cells are often activated even in the absence of systemic inflammation. We suggest that inflammatory stimuli derived from the peripheral blood and the brain parenchyma adjunctly activate vascular cells. Under such circumstances, low-grade inflammation in the pre-existing brain lesions might enhance inflammatory signaling to the brain parenchyma from the periphery. The results of this study could explain the vulnerability of neurological patients to delirium caused by systemic inflammatory conditions.

Aged↗
PubMed2004

Microglial tau undergoes phosphorylation-independent modification after ischemia.

Tau2 is a phosphorylation-independent antibody that immunolabels neurofibrillary tangles (NFTs) of Alzheimer type and microglia around ischemic foci on formalin-fixed, paraffin-embedded sections. We found that copresence of polyethyleneglycol-p-isooctylphenyl ether (Triton X-100; TX) with tau2 abolished its immunoreactivity (IR) in these microglia but not its IR on NFTs. Tau2-immunoreactive bands, exclusively retrieved in Tris-soluble fraction of brain homogenates from ischemic foci, normal human and bovine brains, were of similar electrophoretic mobility, indicating that tau2 IR in these microglia is unrelated to hyperphosphorylation of tau. These tau2-immunoreactive bands except those from bovine brain were abolished in the copresence of TX. This was not due to washing out of tau, because similar immunoreactive bands were detectable with another antitau antibody even under a higher concentration of TX and because washing after TX exposure restored similar tau2 IR both on immunohistochemistry and immunoblot. These findings are explained if tau, modified after ischemia, undergoes a reversible conformational change on TX exposure. Because conformation at Ser101 of bovine tau is crucial for its affinity to tau2, this Ser-like conformation mimicked by its human counterpart Pro may represent pathological modification of tau shared by microglia around ischemic foci and NFTs. Relative resistance of tau2 epitope in NFTs to TX exposure suggests that tau woven into NFTs confers additional stability to this pathological modification on tau2 epitope. Susceptibility of tau2 epitope to TX, seen in these microglia, is shared with glial cytoplasmic inclusions and will show its conformational state to be different from that in NFTs.

Aged↗
PubMed2004

Identification of amino-terminally cleaved tau fragments that distinguish progressive supranuclear palsy from corticobasal degeneration.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative diseases that are characterized by intracytoplasmic aggregates of hyperphosphorylated tau with four microtubule-binding repeats. Although PSP and CBD have distinctive pathological features, no biochemical difference in aggregated tau has been identified. In this study, we examined the brains of eight patients with PSP, six patients with CBD, and one atypical case with pathological features of both CBD and PSP. On immunoblots of sarkosyl-insoluble brain extracts, a 33kDa band predominated in the low molecular weight tau fragments in PSP, whereas two closely related bands of approximately 37kDa predominated in CBD. Immunoblots of the atypical case showed both the 33kDa band and the 37kDa doublet. Protein sequencing and immunochemical analyses showed that the 33kDa band and the 37kDa doublet consisted of the carboxyl half of tau with different amino termini. These results suggest that, despite the identical composition of tau isoforms, different proteolytic processing of abnormal tau takes place in these two diseases. Such a biochemical divergence may be related to the neuropathological features of these diseases.

Aged↗
PubMed2004

Severe acute exacerbation of liver disease may reduce or delay emergence of YMDD motif mutants in long-term lamivudine therapy for hepatitis B e antigen-positive chronic hepatitis B.

The pretherapy factors that could influence the emergence of resistant hepatitis B virus (HBV) tyrosine-methionine-aspartate-aspartate (YMDD) motif mutants against lamivudine are not fully known in prolonged lamivudine therapy for hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. We analyzed prospectively 116 consecutive lamivudine-naïve patients who received long-term lamivudine therapy (>1 year) by using multivariate regression analyses. The cumulative HBeAg loss rates were 29, 44, and 47% at 1, 2, and 3 years of treatment, respectively. Stepwise Cox's regression analyses indicated that pretherapy viral load was a significant factor associated with HBeAg loss (P = 0.0068). The cumulative emergence rates of YMDD mutants were 23% at 1 year, 45% at 2 year, and 47% at 3 year of treatment. Stepwise Cox's regression analyses indicated that patient age and presence or absence of severe acute exacerbation of liver disease were independent significant factors associated with emergence of YMDD mutants (P = 0.018 and 0.048, respectively). For the development of virological breakthrough, patient age, the presence or absence of severe acute exacerbation, and pretherapy viral load were independent significant factors (P = 0.028, 0.043, and 0.044, respectively). Severe acute exacerbation tended to reduce or delay development of biochemical breakthrough. The present study provides important information for the development of more effective and rational long-term lamivudine therapy for HBeAg-positive chronic hepatitis B patients infected exclusively with genotype

Acute Disease↗
PubMed2004

YMDD mutants in patients with chronic hepatitis B before treatment are not selected by lamivudine.

Hepatitis B virus (HBV) mutants with mutations in the YMDD motif of viral DNA polymerase/reverse transcriptase are described in patients infected with HBV who have not received lamivudine therapy, but their pathogenetic potential is not clear. These mutants were detected by the polymerase chain reaction with peptide nucleic acid clamping in pretreatment sera from two patients who later received lamivudine. One patient developed acute exacerbation with hepatic encephalopathy and received lamivudine along with plasma exchange, which were effective on his illness. YIDD mutants were detected in all three pretreatment sera and both posttreatment sera from him. HBV DNA clones from pretreatment and posttreatment sera, however, did not have the same amino acid sequence. In the other patient who developed severe breakthrough hepatitis after receiving lamivudine, YIDD mutants were detected in two pretreatment and two posttreatment sera. When amino acid sequences of HBV DNA clones with the YIDD mutation were compared before and after he received lamivudine, however, they were not in accord. Hence, YIDD mutants in both patients with chronic hepatitis B before treatment were not selected by lamivudine after they had been placed on it. Numerous amino acid conversions were detected in HBV DNA clones with YIDD mutations, and some of them created stop codons in the overlapping S gene sequence. In Conclusion, HBV mutants with mutations in the YMDD motif in patients before treatment would not be selected by lamivudine or induce breakthrough hepatitis, and some of these would not be replication-competent due to stop codons in the S gene.

Adult↗
PubMed2004

Low rate of YMDD motif mutations in polymerase gene of hepatitis B virus in chronically infected patients not treated with lamivudine.

BACKGROUND: Lamivudine is used for the treatment of chronic hepatitis B (CH-B), and exhibits excellent antiviral activity. However, longterm administration increases the likelihood of the emergence of resistant viruses, with an accompanying relapse of hepatitis. However, recent studies have reported lamivudine-resistant viruses in patients with CH-B before such treatment. The aim of this study was to investigate whether YMDD mutants occur in nature. METHODS: The existence of lamivudine-resistant viruses was examined in 20 asymptomatic carriers of hepatitis B virus (ASC), 10 patients who lost hepatitis B surface antigen (HBsAg) during follow-up and in 20 lamivudine-treated patients with and without breakthrough hepatitis. Both polymerase chain reaction (PCR) restriction fragment length polymorphism and SMITEST hepatitis B virus (HBV)-YMDD mutation detection methods were used to detect resistant viruses. RESULTS: No YMDD mutants were detected in the sera of the 20 ASC at the initial and final medical examinations, nor were YMDD mutants detected in sera collected at the initial medical examination, about 6 months before, or immediately after the loss of HBsAg in the 10 patients. In the 20 patients treated with lamivudine, YMDD mutants were not detected in any of them before treatment, whereas mutants were detected in the sera of 10 patients during treatment. CONCLUSIONS: Our results suggest that lamivudine-resistant YMDD mutant viruses were present in a few patients with HBV infection before they have been treated with lamivudine.

Adult↗
PubMed2004

High-dose interferon alpha-2b induction therapy in combination with ribavirin for Japanese patients infected with hepatitis C virus genotype 1b with a high baseline viral load.

BACKGROUND: Although pegylated interferon (IFN) is now used in many countries as a standard therapy for chronic hepatitis C, the efficacy and safety of combination therapy of high-dose interferon alpha-2b induction with ribavirin are not fully evaluated, especially in Japanese patients infected with hepatitis C virus (HCV) genotype 1b with a high viral load. METHODS: Patients ( n = 83) received daily, high-dose induction therapy of interferon alpha-2b (6 million units [MU] once daily for 2 weeks), followed by 6 MU three times weekly for 22 weeks. Oral ribavirin (800 or 600 mg/day) was given daily for 24 weeks, and then the patients were followed up for 24 weeks. RESULTS: Of the 83 patients, 67 (81%) had a biochemical response (BR), and 37 (45%) achieved a sustained BR (SBR). Virologic response (VR; undetectable serum HCV RNA level by polymerase chain reaction [PCR]) was noted in 55 (66%) patients, and sustained VR (SVR) in 16 (19%) patients. Baseline viral load did not influence treatment outcome. There was no significant difference in treatment outcome among treatment-naIve patients, relapsers, and nonresponders to previous IFN monotherapy. Multivariate analyses identified serum ribavirin concentrations at week 8 of therapy (odds ratio [OR], 23.7; 95% confidence interval [CI], 1.84-61.1; P = 0.015) and negativity for serum HCV RNA at week 8 (OR, 22.5; CI, 1.76-57.5; P = 0.017, respectively) as two significant and independent predictors of SVR. CONCLUSIONS: The efficacy of 24-week combination therapy of high-dose IFN alpha-2b induction and ribavirin deserves attention in HCV genotype 1b patients with a high viral load, especially in nonresponders to previous IFN monotherapy and patients with a very high viral load.

Adult↗
PubMed2004

Efficacy of interferon retreatment after relapse for chronic hepatitis C patients with biochemical response after first interferon therapy.

BACKGROUND: With respect to interferon (IFN) treatment for chronic hepatitis C, normalization of alanine aminotransferase (ALT) as well as clearance of hepatitis C virus (HCV)-RNA after IFN therapy is important. It has been shown that the incidence of hepatocellular carcinoma (HCC) in patients with normal ALT is significantly lower than that in those with elevated ALT after IFN therapy. We assessed the efficacy of IFN retreatment for chronic hepatitis C patients who had a biochemical response (BR) after the first IFN therapy and reelevated ALT during follow up, by a case control study. METHODS: Fifteen patients (case group; group 1) enrolled in this study showed a BR after the first IFN therapy and reelevated ALT during follow up. Next, we retrospectively selected 30 patients (control group; group 2) with no response (NR) after the first IFN therapy. Group 2 patients were matched 1 : 2 with group 1 patients for sex and age. All patients were given intramuscular injections of human lymphoblastoid IFN alpha daily (6 MU) for 8 weeks and then three times a week for 16 weeks. We compared the clinical and biological differences between group 1 patients and group 2 patients. Virological response (VR) was defined when serum HCV-RNA showed negativity more than 6 months after the completion of IFN therapy. BR was defined when ALT values remained normal during more than 6 months in spite of positive serum HCV-RNA, by reverse-transcription nested polymerase chain reaction, 3 and 6 months after the completion of IFN therapy. NR was defined as any response except for VR or BR. RESULTS: The rate of patients showing VR in this study was 6.7% (1/15) in group 1 and 13.3% (4/30) in group 2. There was no significant difference between the groups with respect to VR. BR occurred in 73.3% (11/15) of patients in group 1, but in only 3.3% (1/30) of patients in group 2 (P = 0.0002). CONCLUSIONS: We conclude that IFN retreatment is one of the effective strategies with which to achieve BR again in HCV-positive patients who had a BR after their first IFN therapy and reelevation of ALT during follow up.

Adult↗
PubMed2004

Hepatocellular carcinoma in noncirrhotic young adult patients with chronic hepatitis B viral infection.

BACKGROUND: The aims of this study were to define the clinical characteristics of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in young adult patients without cirrhosis and to evaluate the efficacy of interferon (IFN) therapy on HCC recurrence. METHODS: Of 187 patients with HBV-related HCC treated at our hospital, 4 had no liver cirrhosis and were less than 30 years of age (10, 22, 23, and 26 years). RESULTS: At the time of diagnosis of HCC, all cases had antibody to hepatitis B e antigen (anti-HBe) and histological staging of nontumorous liver was F0 or F1, i.e., low-grade hepatitis. The mothers of all 4 young adult patients with HCC had HBV-related liver disease. Three cases developed recurrence of HCC. In these patients, long-term intermittent IFN therapy after reresection of HCC resulted in long-term survival without recurrence for more than 3 years of follow-up. CONCLUSIONS: (1) Young adult patients with HCC are positive for anti-HBe, lack cirrhosis, and the route of infection seems to be mother-to-infant transmission. Transplacental transmission of HBV and HBV DNA integration into the cellular genomic DNA during fetal life is a possible explanation of HBV-related hepatocarcinogenesis in young adults; and (2) long-term IFN therapy seems to be useful for prevention of tumor recurrence after radical operation for HBV-related HCC.

Adolescent↗
PubMed2004

Peripheral CD8+/CD25+ lymphocytes may be implicated in hepatocellular injuries in patients with acute-onset autoimmune hepatitis.

BACKGROUND: The mechanism of liver injuries in autoimmune hepatitis (AIH) is not fully understood, especially because the onset is insidious and the clinical courses fluctuate with spontaneous exacerbation and improvement even without immunosuppressive therapies. METHODS: Eleven patients with acute-onset AIH, some of whom were without hypergammaglobulinemia or anti-nuclear antibodies, and 41 patients with chronic AIH were compared serologically, biochemically, and histologically to determine differences in liver injuries between patients with acute-onset and chronic AIH. All patients fulfilled the diagnostic criteria according to a scoring system proposed in 1999. RESULTS: Lymphocytes with CD8+/CD25+ markers in pretreatment blood were significantly more prevalent in acute-onset than chronic AIH patients (24% vs 14%; P < 0.05). After treatment, however, CD8+/CD25+ lymphocytes were fewer in patients with acute-onset than in those with chronic AIH at 1 and 2 weeks ( P = 0.0001). No other differences were noted in clinical characteristics or immunological parameters between patients with acute-onset and those with chronic AIH. In a patient with typical acute-onset AIH, CD8+/CD25+ lymphocytes increased and decreased in parallel with the activity of liver disease. CONCLUSIONS: Activated CD8+ T lymphocytes with CD25 markers may be implicated in the development of acute-onset AIH.

Acute Disease↗