Biomedical subjects

K Takakura

Publications and source records attributed to K Takakura.

At least 55 records · Page 3Linked to original sources

PubMed2000

Gamma knife surgery for epilepsy related to hypothalamic hamartomas.

OBJECTIVE: Drug-resistant epilepsy associated with hypothalamic hamartomas (HHs) can be cured by microsurgical resection of the lesions. Morbidity and mortality rates for microsurgery in this area are significant. Gamma knife surgery (GKS) is less invasive and seems to be well adapted for this indication. METHODS: To evaluate the safety and efficacy of GKS to treat this uncommon pathological condition, we organized a multicenter retrospective study. Ten patients were treated in seven different centers. The follow-up periods were more than 12 months for eight patients, with a median follow-up period of 28 months (mean, 35 mo; range, 12-71 mo). All patients had severe drug-resistant epilepsy, including frequent gelastic and generalized tonic or tonicoclonic attacks. The median age was 13.5 years (range, 1-32 yr; mean, 14 yr) at the time of GKS. Three patients experienced precocious puberty. All patients had sessile HHs. The median marginal dose was 15.25 Gy (range, 12-20 Gy). Two patients were treated two times (at 19 and 49 mo) because of insufficient efficacy. RESULTS: All patients exhibited improvement. Four patients were seizure-free, one experienced rare nocturnal seizures, one experienced some rare partial seizures but no more generalized attacks, and two exhibited only improvement, with reductions in the frequency of seizures but persistence of some rare generalized seizures. Two patients, now seizure-free, were considered to exhibit insufficient improvement after the first GKS procedure and were treated a second time. A clear correlation between efficacy and dose was observed in this series. The marginal dose was more than 17 Gy for all patients in the successful group and less than 13 Gy for all patients in the "improved" group. No side effects were reported, except for poikilothermia in one patient. Behavior was clearly improved for two patients (with only slight improvements in their epilepsy). Complete coverage of the HHs did not seem to be mandatory, because the dosimetry spared a significant part of the lesions for two patients in the successful group. CONCLUSION: We report the first series demonstrating that GKS can be a safe and effective treatment for epilepsy related to HHs. We advocate marginal doses greater than or equal to 17 Gy and partial dose-planning when necessary, for avoidance of critical surrounding structures.

Adolescent↗

PubMed1999

Rapid and irreversible inactivation of protein tyrosine phosphatases PTP1B, CD45, and LAR by peroxynitrite.

Protein tyrosine phosphatases (PTPs) contain an essential thiol in the active site which may be susceptible to attack by nitric oxide-derived biological oxidants. We assessed the effects of peroxynitrite, nitric oxide, and S-nitrosoglutathione on the activity of three human tyrosine phosphatases in vitro. The receptor-like T-cell tyrosine phosphatase (CD45), the non-receptor-like tyrosine phosphatase PTP1B, and leukocyte-antigen-related (LAR) phosphatase were all irreversibly inactivated by peroxynitrite in less than 1 s with IC(50) values of </=0.9 microM. PTP inactivation was also seen with equivalent concentrations of peroxynitrite generated by SIN-1, indicating that bolus peroxynitrite and cogeneration of superoxide and nitric oxide were equipotent. Rate constants for peroxynitrite-mediated PTP inactivation were determined by competition with cysteine and were among the fastest rates yet seen for reaction of peroxynitrite with any biological molecules. The bimolecular reaction rates for CD45, LAR, and PTP1B were 2.0 x 10(8), 2.3 x 10(7), and 2.2 x 10(7) M(-1) s(-1), respectively. Inactivation by peroxynitrite was essentially irreversible as incubation with dithiothreitol (DTT) restored less than 10% of the original phosphatase activity. Prolonged treatment with 0.4 mM DETA NONOate, which generated a steady-state concentration of 2 microM nitric oxide, was only slightly inhibitory. S-Nitrosoglutathione (1.0 mM) inhibited PTPs by approximately 50% after 30 min and the inhibition was completely reversed by DTT. Nitrotyrosine immunoblots of peroxynitrite-treated PTP1B revealed that peroxynitrite completely inactivated PTP1B prior to the appearance of protein tyrosine nitration. Peroxynitrite anion is structurally similar to phosphate anion both in terms of molecular diameter and charge. Thus, the extreme vulnerability of these PTPs to peroxynitrite-mediated inactivation is consistent with attraction of peroxynitrite anion to the active site and subsequent oxidation of the essential thiolate. These findings suggest that any PTP possessing the CXXXXXR active-site sequence could potentially be inactivated by peroxynitrite in vivo resulting in a net increase in tyrosine phosphorylation and profound effects on phosphotyrosine-dependent signaling cascades.

Aniline Compounds↗

PubMed1999

Postoperative flow cytometry crossmatch in living donor liver transplantation: clinical significance of humoral immunity in acute rejection.

BACKGROUND: The role of humoral immunity in acute rejection in solid organ transplantation remains controversial, although it is known that the presence of antidonor antibodies may precipitate graft rejection. We investigated the clinical relevance of antidonor humoral immunity for living donor liver transplantation (LDLT) by means of flow cytometry crossmatch (FCXM). METHODS: T cell FCXM using fresh donor peripheral lymphocytes was performed before and up to 1 month after LDLT in 58 patients. Ten patients received ABO-incompatible grafts. IgM and IgG antidonor antibodies were analyzed in relation to clinical acute rejection as defined by liver function tests with or without histological evidence. RESULTS: Pretransplantation FCXM was positive for five patients (8.6%), resulting in two cases of positive posttransplantation FCXM and two rejection episodes. Twelve patients (20.7%) showed positive posttransplantation FCXM. The incidence of acute rejection within 1 month was 100% in FCXM-positive patients and 17.4% in FCXM-negative patients (P<0.001). Thirteen (76.5%) of 17 rejection episodes in ABO-compatible cases were associated with concomitant antidonor IgM antibody. IgG antibody was also identified in six of these episodes. Antidonor antibodies disappeared after rejection treatments in all cases, but with some delay in clinical improvement. On the other hand, no antidonor antibodies were detected in any of the four rejection episodes in ABO-incompatible cases. CONCLUSIONS: Early acute rejection in LDLT is significantly associated with antidonor T cell antibody formation in ABO-compatible cases. This suggests a definite role for donor-specific humoral immunity in acute rejection. Rejection episodes without antidonor antibodies may suggest graft injury by pure cellular immunity, or possibly the presence of humoral immunity triggered by antigens not present on donor T cells.

ABO Blood-Group System↗

PubMed1999

Phenytoin as a liquid material for embolisation of tumours.

We carried out embolisation with phenytoin in seven patients with meningiomas; in three by cannulation of the middle meningeal artery during surgery and in four by microcatheter introduced into the middle meningeal artery. Phenytoin (125-500 mg) diluted with saline (25 mg/ml) was injected slowly as a bolus. There was no evidence of devascularisation in two meningiomas treated with 125 mg and 150 mg of phenytoin. Large areas of ischaemic and haemorrhagic necrosis were found in five meningiomas treated with 250-500 mg. After embolisation, the tumour blush disappeared, with preservation of the feeding arteries. Total resection of the tumour was performed with minimum blood loss. Caution and proper use are emphasised to avoid increase in tumour volume and reflux. Phenytoin could be a suitable material for superselective embolisation.

Adult↗

PubMed1999

Possible involvement of nitroglycerin converting step in nitroglycerin tolerance.

Nitroglycerin (GTN) produces a dilation of vascular smooth muscle by releasing NO through a putative GTN-converting step. However, the response to GTN is markedly attenuated after prolonged or repeated exposure, resulting in tolerance. We investigated the mechanisms of GTN tolerance, employing exogenous and endogenous NO in rat aorta. In endothelium-denuded rat aortic strips, the GTN-induced relaxation response was attenuated by preceding exposure to either GTN or sodium nitroprusside (SNP). In contrast, the SNP-induced relaxation response was not affected by this protocol of GTN or SNP preexposure. Preincubation of aortic strips with lipopolysaccharide (LPS) +/- L-arginine for 12 h also caused attenuation of GTN-induced responses such as relaxation, cGMP production and nitrite/nitrate formation. The attenuating effect of LPS abolished in aortic strips co-incubated with LPS and cycloheximide or N(G)-nitro-L-arginine. These results suggest that GTN tolerance is predominantly associated with the reduction of NO release from GTN, which is caused through inhibition of a GTN-converting step due to preceding exposure to NO itself.

Animals↗

PubMed1999

DNA flow cytometric quantification and DNA polymorphism analysis in the case of a complete mole with a coexisting fetus.

PURPOSE: Our purpose was to investigate whether DNA flow cytometric quantification and DNA polymorphism analysis are useful for cytogenetic diagnosis in the case of a complete hydatidiform mole that coexists with a living fetus. METHODS: Flow cytometric analysis of the nuclear DNA content and polymerase chain reaction (PCR) amplification of the minisatellite locus with the MCT118 probe were performed on the tissues (fetus, placenta and mole) obtained at the initial evacuation. RESULTS: DNA histograms of placental, fetal, and molar tissues showed diploid peaks. PCR products demonstrated that the allele of the mole was homozygous and inherited solely from the husband and that the mole differed genetically from the fetus and the placenta. CONCLUSIONS: These results suggested that DNA flow cytometry and DNA polymorphism analysis may be useful for the cytogenetic diagnosis of a complete hydatidiform mole and a coexisting fetus.

Adult↗

PubMed1999

Target cells for an immunosuppressive cytokine, glycosylation-inhibiting factor.

Receptors for bioactive glycosylation-inhibiting factor (GIF) were demonstrated using a bioactive mutant of recombinant human (rh) GIF, which is comparable to the suppressor T (Ts) cell-derived bioactive GIF in its affinity for the receptors on helper T (Th) hybridoma cells. Both naive T and B cells in normal mouse spleen lacked GIF receptors. However, presentation of specific antigen to naive T cells resulted in the expression of the receptors on activated T cells. Furthermore, activation of small resting B cells with F(ab')2 fragments of anti-mouse IgM plus IL-4, lipopolysaccharide (LPS) plus IL-4 or LPS plus dextran sulfate induced the expression of the receptors within 48 h of B cell stimulation. It was also found that NK T cells freshly isolated from mouse spleen, but not conventional NK cells, expressed receptors for GIF. CD4(+) and CD4(-) subpopulations of NK T cells showed a similar binding capability. Mature dendritic cells derived from bone marrow did not bear the receptors. The dissociation constant (Kd) of the interaction between the bioactive rhGIF mutant and the high-affinity receptors was 10-100 pM, whereas inactive wild-type rhGIF failed to bind to the receptors. A bioactive derivative of rhGIF suppressed both IgG1 and IgE synthesis by purified B cells activated by LPS and IL-4, indicating that the binding of bioactive GIF to its receptors on activated B cells results in suppression of their differentiation.

Animals↗

PubMed1999

Identification of genes differentially expressed in canine vasospastic cerebral arteries after subarachnoid hemorrhage.

To understand the molecular processes of continuous vasospasm of cerebral arteries after subarachnoid hemorrhage, mRNA differential display and screening of cDNA expression array were performed to identify genes that are differentially expressed in vasospastic arteries of canine two-hemorrhage models. The expression levels of 18 genes were found to be upregulated, and those of two genes to be downregulated. Of these, 12 represent known genes or homologues of genes characterized previously, and the other eight genes are not related to any sequences in the databases. The known genes include five upregulated inflammation-related genes encoding monocyte chemotactic protein-1, cystatin B, inter-alpha-trypsin inhibitor family heavy chain-related protein, serum amyloid A protein, and glycoprotein 130, suggesting that inflammatory reaction may be involved in the development of cerebral vasospasm. The upregulation of three known genes encoding stress-related proteins of vascular endothelial growth factor, BiP protein, and growth-arrest and DNA-damage-inducible protein may be involved in possible cell survival in the damaged arteries. A full-length cDNA for the unknown clone DVS 27, whose expression was most highly upregulated, was isolated from the cerebral artery cDNA library by hybridization. Characterization of these genes should help to clarify the molecular mechanism of continuous cerebral vasospasm after subarachnoid hemorrhage.

Amino Acid Sequence↗

PubMed1999

Angles between A1 and A2 segments of the anterior cerebral artery visualized by three-dimensional computed tomographic angiography and association of anterior communicating artery aneurysms.

OBJECTIVE: The angle of arteries at bifurcations, as well as the blood flow, are factors of hemodynamic stress on the apical region, where aneurysms often develop. Using images obtained with three-dimensional computed tomographic angiography, we sought to determine the angles between the A1 and A2 segments of the anterior cerebral artery of the anterior communicating artery (ACoA) complex associated with aneurysms. These angles cannot be detected by conventional cerebral angiography. METHODS: The course of the anterior cerebral artery was studied using three-dimensional computed tomographic angiography in 42 consecutive patients with ACoA aneurysms. Twenty-one other subjects, randomly chosen from patients without aneurysms, served as controls. Bilateral A1-A2 angles of the contrast-opacified anterior cerebral artery were measured by three-dimensional computed tomographic angiography in patients with normoplastic A1 segments, and the relationship between the angle and the association of aneurysms was analyzed using cerebral angiography. RESULTS: Of the 42 patients with ACoA aneurysms, 19 patients showed hypo- or aplastic A1 segments, as did only 2 of the 21 patients without ACoA aneurysms. The average A1-A2 angle was determined to be 116+/-24 degrees (mean+/-standard deviation) in 18 patients having ACoA complexes with normoplastic A1 segments with aneurysms; 17 patients without aneurysms had A1-A2 angles measuring 143+/-14 degrees (P < 0.0001). The A1-A2 angle associated with ACoA aneurysms was 103+/-20 degrees, which was much smaller than that of the non-aneurysm side in the former group (128+/-20 degrees) (P = 0.0036). CONCLUSION: ACoA aneurysms are associated with the smaller A1-A2 angle junction of the ACoA complex, where higher hemodynamic stress may occur in patients with normoplastic A1 segments.

Adult↗

PubMed1999

Effects of size and shape (aspect ratio) on the hemodynamics of saccular aneurysms: a possible index for surgical treatment of intracranial aneurysms.

OBJECTIVE: The present study was undertaken to explore the relationship between the characteristic geometry of aneurysms prone to rupture and the blood flow patterns therein, using microsurgically produced aneurysms that simulated human middle cerebral artery aneurysms in scale and shape. METHODS: We measured in vivo velocity profiles using our 20-MHz, 80-channel, Doppler ultrasound velocimeter. We produced small (< or =5 mm, 5 cases) and large (6-13 mm, 12 cases) aneurysms with round, dumbbell, or multilobular shapes. RESULTS: The fundamental patterns of intra-aneurysmal flow were composed of inflow, circulating flow, and outflow. The inflow, which entered the aneurysm only during the systolic phase, was strongly influenced by the position and size of the neck and the flow ratio into the distal branches. The outflow was usually nonpulsatile and of low velocity. The circulating flow depended on the aspect ratio (depth/neck width). A single recirculation zone was observed in aneurysms with aspect ratios of less than 1.6. This circulation did not seem to extend to areas with aspect ratios greater than this value; in aneurysms with aspect ratios of more than 1.6, a much slower circulation was observed near the dome. Furthermore, in the dome of dumbbell-shaped aneurysms and daughter aneurysms, no flow was detected. Intra-aneurysmal flow was determined by the aspect ratio, rather than the aneurysm size. CONCLUSION: The localized, extremely low-flow condition that was observed in the dome of aneurysms with aspect ratios of more than 1.6 is a common flow characteristic in the geometry of ruptured aneurysms, so great care should be taken for patients with unruptured intracranial aneurysms with aspect ratios of more than 1.6.

Aneurysm, Ruptured↗

PubMed1999

Expression of macrophage inflammatory protein-1alpha (MIP-1alpha) in human endometrium throughout the menstrual cycle.

OBJECTIVE: To investigate the distribution and the role of macrophage inflammatory protein-1alpha (MIP-1alpha) in human endometrium during cyclic changes. SETTING: Department of Obstetrics and Gynaecology, Shiga University of Medical Science and University Hospital. MATERIALS: Eighteen endometrial tissue specimens surgically resected or biopsied from women with normal menstrual cycles, without hormonal disorder or endometrial diseases. METHODS: By immunohistochemistry, using monoclonal antibodies (lambda delta 78 for MIP-1alpha and CR3/43 for human leukocyte antigen-DR (HLA-DR)). RESULTS: Immunoreactivity for anti-MIP-1alpha was distributed diffusely in epithelial cells throughout the proliferative and secretory phases but was absent during menstruation due to degenerative or necrotic changes. HLA-DR was expressed in epithelial cells only in the late secretory phase and was not expressed in stromal cells. CONCLUSION: Immunohistochemical analysis showed the presence of MIP-1alpha in the endometrial epithelium. Expression of HLA-DR in epithelial cells was observed only in the late secretory phase, suggesting that accumulation of MIP-1alpha in epithelium occurred by self production and not via a receptor mediated pathway. MIP-1alpha was released from the denuded epithelium during menstruation and appeared to contribute to the accumulation of monocytes/macrophages into the endometrial cavity. MIP-1alpha has a number of biological effects other than monocytic chemotaxis, and some of these effects may be exerted in the endometrial tissue.

Biomarkers↗

PubMed1999

Low-dose radiosurgery for meningiomas.

Gamma Knife radiosurgery is an effective treatment for meningiomas. However, it may be difficult to deliver what is currently considered an optimal dose, especially if the tumor is large or adjacent to critical structures. Eleven cases are presented with a follow-up of more than 12 months where the margin dose did not exceed 10 Gy. The mean age was 48.8 years. The mean follow-up period was 35.7 months (range 21 to 57 months). The mean volume of the tumors was 9.4 cm3 (range 1.6 to 28.9 cm3). The margin dose was less than 10 Gy in all 11 cases, due to a large volume in two cases. Four tumors were close to the visual pathways. Five tumors were close to the brain stem. Imaging follow-up showed that four tumors had shrunk after radiosurgery. The remaining seven cases remained unchanged. There was no tumor growth after radiosurgery. A transient oculomotor palsy was observed in two cases after radiosurgery. It is suggested that Gamma Knife radiosurgery using lower dosage than usual is one of the options for the treatment of meningioma.

Adult↗

PubMed1999

Gamma Knife radiosurgery for pituitary adenomas.

Ninety-two patients with pituitary adenomas have been treated during the last 5 years. Sixty-three of these patients had more than 6 months follow-up, and they form the basis of this report. Eighteen had non-functioning adenomas (NFA), and 36 had functioning adenomas (FA). The mean marginal dose was 22.5 Gy (NFA 19.5 Gy, FA 23.9 Gy). Control of tumor growth was achieved in 92%. A significant decrease of excessive hormone production was seen in 75.6%, and the endocrinopathy normalization rate was 26.7%. Post-radiosurgical complications were seen in 4.7%.

Acromegaly↗

PubMed1999

Heterozygous gsp mutation renders ion channels of human somatotroph adenoma cells unresponsive to growth hormone-releasing hormone.

Ionic mechanisms play an important role in the regulation of hormone secretion. The GHRH-induced GH release by human GH-secreting cells is transmitted through protein kinase A (PKA), which activates nonselective cation current (NSCC) and induces membrane depolarization, intracellular Ca2+ increase, and GH secretion. To evaluate whether ionic mechanisms have pathophysiological significance in GH oversecretion of GH-secreting pituitary adenomas, we examined four adenomas with constitutively active Gs alpha mutation (gsp mutation) and compared with three gsp-negative adenomas. In primary-cultured cells of gsp-positive adenomas, GHRH did not increase the NSCC under voltage-clamp experiments. Detailed examination showed that NSCC was maximally activated at the basal level and application of GHRH did not increase the current in these adenomas. Furthermore, by using single-cell RT-PCR method, we demonstrated for the first time at the single cell level that gsp mutation is heterozygous in GH-secreting pituitary adenomas. These indicate that heterozygous gsp mutation fully activates NSCC at the basal level, which may account for the GH oversecretion in gsp-positive GH-secreting pituitary adenomas.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1999

Pharmacological comparison between the nitrergic responses produced by intramural nerve stimulation and exogenous NO-donors in rat gastric fundus.

To investigate whether the nitrergic nerve-mediated smooth muscle relaxation is caused by authentic nitric oxide (NO) and is mediated via guanosine 3':5'-cyclic monophosphate (cyclic GMP), we compared the response to electrical field stimulation of nitrergic nerve (EFS) with other NO-related responses in rat gastric fundus strips. EFS, sodium nitroprusside (SNP), S-nitroso-N-acetylpenicillamine (SNAP), and acidified NaNO2 and inducible NO synthase (iNOS)-mediated NO all produced relaxation and elevated cyclic GMP level in rat fundus strips. However, the basal and stimulated cyclic GMP levels were significantly lower than the basal level in aorta (40+/-4 pmol/g wet tissue). Methylene blue and 6-anilino-5,8-quinolinedione (LY83583), both known as soluble guanylyl cyclase inhibitors and O2- generators that scavenge NO, reduced the elevation of cyclic GMP level by all stimuli and inhibited the relaxations only in response to NaNO2 and iNOS-mediated NO but not to the other stimuli. These results suggest that in the rat gastric fundus strips the relaxations induced by not only nitrergic nerve but also SNP and SNAP are not associated with cyclic GMP production, in contrast to the relaxations mediated by authentic NO.

Animals↗

PubMed1999

Embryo-dependent induction of embryo receptivity in the mouse endometrium.

The effect of intraoviductal embryos on endometrial receptivity was studied by intraendometrial and intrauterine embryo transfer. Five-week-old female ICR mice were mated after superovulation; a vaginal plug confirmed day 1 of pregnancy. On day 4 (90 h after hCG injection), blastocysts were collected and transferred to pseudopregnant female mice and to recipient mice in which the uterotubal junction had been ligated bilaterally on day 1 of pregnancy. Three embryos per uterine horn, a total of six embryos per recipient mouse at days 1-6, were transferred to the endometrium or uterine cavity and implantation and pregnancy rates were calculated. The implantation rate for intraendometrial embryo transfer to recipients of days 3, 5 and 6 was significantly higher for uterotubal junction-ligated mice (72.2, 20.8 and 9.7%, respectively) than for pseudopregnant mice (55.0, 8.3 and 0.0%, respectively). The implantation rate for intrauterine embryo transfer to recipients at days 2, 5 and 6 was significantly higher for uterotubal junction-ligated mice (11.1, 25.0 and 8.3%, respectively) than for pseudopregnant mice (0.0, 3.3 and 0.0%, respectively). Uterotubal junction-ligated mice achieved implantation and bore neonates by intrauterine embryo transfer on days 2 and 6, whereas no implantation was achieved in pseudopregnant mice. The difference in implantation rate could not be explained by a difference in progesterone concentration between the groups. The distribution of proliferating cells in the endometrium was also studied immunohistochemically by use of anti-proliferating cell nuclear antigen (PCNA) antibody in the recipient mice. PCNA-positive cells were more abundant in uterotubal junction-ligated mice and demonstrated a marked extension from the epithelium to the stroma over time, in contrast to those in pseudopregnant mice. These findings indicate that an intraoviductal embryo exerts a biological effect by sending a signal to the endometrial epithelium and stroma, thus facilitating endometrial receptivity to the embryo and improving the rate of implantation.

Animals↗

PubMed1999

Primary central nervous system T-cell lymphoma. Case report.

A 46-year-old male presented with a rare primary non-Hodgkin's lymphoma of the central nervous system of T-cell lineage, localized primarily in the right parietal region. There was no evidence of acquired immunodeficiency syndrome. Biopsy of the tumor allowed immunohistochemical confirmation of the diagnosis. Irradiation and chemotherapy were given, and the patient has remained well for 24 months. The clinical manifestations, management, and outcome of T-cell lymphoma are very similar to those of B-cell lymphoma.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1999

Sudden death in a rat subarachnoid hemorrhage model.

The pathogenesis of sudden death during subarachnoid hemorrhage (SAH) still remains to be elucidated. A new rat common carotid artery-prechiasmal extracorporeal shunt model was designed to study the effect of different severities of SAH on intracranial pressure (ICP), regional cerebral blood flow (rCBF), and mortality. Different severities of SAH were induced by controlling the bleeding period (from 30 to 90 sec) and number of bleedings (one or three times). SAH caused a dramatic increase in ICP and immediate depression of rCBF, which recovered slowly to a certain extent. ICP increased sharply within the first 30 seconds and reached a plateau concomitant with nearly zero rCBF, which suggested the occurrence of cerebral circulation arrest. Bleeding of more than 60 seconds and increased ICP over 80 mmHg were directly correlated with the mortality. Respiratory arrest was the first sign of death, immediately followed by cardiac depression resulting in sudden death. This model combines arterial bleeding with systemic blood pressure and controlled bleeding time to simulate the acute period of SAH.

Acute Disease↗