[Hepatotoxicity induced by non-steroidal anti-inflammatory drugs].
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Anti-Inflammatory Agents, Non-Steroidal↗
Biomedical subjects
H Tanno
Publications and source records attributed to H Tanno.
Pediatric and adult forms of type I autoimmune hepatitis in Argentina: evidence for differential genetic predisposition.
The aim of this study was to compare major histocompatibility complex (MHC) class II susceptibility to type 1 autoimmune hepatitis (AH) between children and adults of the same ethnic group. HLA-DRB1, HLA-DRB3, HLA-DQA1, and HLA-DQB1 gene subtypes were examined by high resolution oligonucleotide typing in 122 pediatric (PAH) and 84 adult (AAH) patients and in 208 controls. In children, HLA-DRB1*1301 was the primary susceptibility allele (66.4% patients vs. 10.6% controls, relative risk [RR] = 16.3, Pc < 10(-24)) whereas HLA-DRB1*1302, which differs from HLA-DRB1*1301 by only 1 amino acid, appeared to be protective. The exclusion of individuals with HLA-DRB1*1301 from control and pediatric patients allowed us to find a secondary association of PAH with HLA-DRB1*0301. Possession of HLA-DRB1*1301, however, was associated with a lower therapeutic response rate. Analysis of peptide binding pocket residues indicated that Tyr 10, Ser 11, Ser 13, and Val 86 in the class II beta chain were present in 85% of patients compared with 37% of controls, suggesting that a high proportion of AH susceptibility is attributable to these residues (etiologic fraction [EF] = 76%). In contrast to the class II associations in children, AAH was associated with HLA-DRB1*0405 (RR = 10.4, Pc <.005) but not with HLA-DRB1*1301 or HLA-DRB1*0301. In addition, HLA-DR4 with the class I gene, HLA-A11, appeared synergistic in predisposing AAH patients to develop extra-hepatic autoimmune (AI) manifestations (odds ratio [OR] = 104.9, Pc < 10(-4)). Concomitant differences in autoantibody profiles were also observed in PAH versus AAH: smooth muscle antibodies (SMA) were most prevalent in PAH but antinuclear antibodies were most prevalent in AAH (P =.003). This study therefore reveals that different HLA-DRB1 allotypes confer susceptibility to AH in children and adults and raises the possibility that PAH and AAH may be triggered by different factors.
Adult↗
Prognostic value of hepatic venous pressure gradient measurements in alcoholic cirrhosis: a 10-year prospective study.
BACKGROUND & AIMS: Different parameters are considered predictors of bleeding and death in alcoholic cirrhosis. The aim of this study was to establish the prognostic value of a prospective and sequential evaluation of portal pressure, variceal size, and Pugh's score in portal-hypertensive patients with alcoholic cirrhosis but no previous bleeding. METHODS: Thirty patients were evaluated for 42 +/- 5 months (median, 39 months). After baseline studies, 30 patients underwent an additional evaluation (follow-up 1; median, 10 months), 20 patients a second evaluation (follow-up 2; median, 25 months), and 13 patients a third evaluation (follow-up 3; median, 45 months). No prophylactic treatment for bleeding was given. End points were bleeding and/or death. RESULTS: Seventeen patients died, and 10 patients bled. At follow-up 1, portal pressure decreased both in survivors and nonbleeders (from 18.7 +/- 1.0 to 15.2 +/- 1.3 mm Hg [P < 0.01] and from 18.9 +/- 0.8 to 16.5 +/- 1.0 mm Hg [P < 0.05], respectively). On multivariate analysis (Cox model), portal pressure at follow-up 1 had the best prognostic and independent value for both bleeding and survival. Subsequent studies showed similar trends. CONCLUSIONS: Measurements of portal pressure provide unique prognostic information for predicting portal hypertensive-related bleeding and mortality in patients with alcoholic cirrhosis.
Adult↗
Reactive astrocytes in acute stage after experimental brain injury: relationship to extravasated plasma protein and expression of heat shock protein.
It is well known that an astrocytic response occurs after brain damage; however, the mechanisms initiating this acute astrocytic response remain unclear. In this study, we examined the immunolocalization of glial fibrillary acidic protein (GFAP) to investigate the astrocytic response within 72 h after injury. Further, we related these results to the distribution of extravasated plasma protein and the expression of stress protein. Adult male Wistar rats were subjected to a lateral fluid percussion brain injury. Animals were sacrificed at 1, 6, 24, and 72 h postinjury. Each brain section was immunostained for GFAP, extravasated albumin, and heat shock protein (HSP 72). Immunoreactive astrocytes, extravasated albumin, and HSP 72 positive cells were evaluated by light microscopy. Reactive astrocytes were defined by the presence of increased immunoreactivity to anti-GFAP. By 6 h, the presence of reactive astrocytes was restricted to the impact site and the hemorrhagic external capsule. At 24 h, reactive astrocytes were identified in the entire injured hemisphere. By 72 h, the immunoreactive astrocytes were more pronounced than at 24 h. At 1 h, extravasated albumin was found at the impact site, the hemorrhagic external capsule, the parasagittal cortex, hippocampus, thalamus, and midbrain. By 72 h, the immunostaining of albumin was more widely distributed. HSP 72 immunoreactive glia were detected only at the impact site and the hemorrhagic external capsule. In summary, the distribution of reactive astrocytes at 6 h was associated with HSP 72-positive glia rather than the extravasation of albumin. In contrast, the distribution of reactive astrocytes at 24 and 72 h paralleled that of extravasated albumin. These results suggest that the initial response of astrocytes is correlated to glial stress and/or injury and that humoral factors play a role in the subsequent responses.
Animals↗
[Characteristics of childhood asthma and guideline for its management].
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Adolescent↗
The blood-brain barrier disruption to circulating proteins in the early period after fluid percussion brain injury in rats.
Breakdown of the blood-brain barrier (BBB) immediately after traumatic brain injury is not clearly understood. In the present study we focused on the integrity of the BBB to circulating proteins within the first hour after injury. For this purpose, vascular permeability to endogenous albumin and to the exogenous protein tracer horseradish peroxidase (HRP) was examined after a lateral fluid percussion brain injury in rats. Albumin was immunolocalized in brain sections at 3 and 60 min after impact. This distribution was compared with the histochemical localization of HRP given before impact at the same time points. In a separate experiment HRP was given prior to sacrifice to determine the time course for the barrier disruption. Permeability to this protein was assessed at 13, 30, and 60 min after impact. Prominent extravasation of albumin occurred within 3 min of injury and was present in multiple foci within the injured hemisphere. At 60 min the extravasated albumin was present in the same sites, where it was widely distributed. Throughout the related brain parenchyma, little difference was found between the extravascular distribution of albumin and HRP. In the delayed administration paradigm breakdown of the BBB was noted in the impact site, hemorrhagic site in the deep cortical layer, hippocampus, thalamus, and midbrain at 13 min after injury. This injured barrier was restored in most regions by 30 min. However, the impact site and hemorrhagic site remained permeable up to 60 min postinjury. In addition, newly developed barrier disruption to HRP occurred in the parasagittal cortex at 30 and 60 min. In conclusion, widespread breakdown of the BBB to circulating proteins occurred within a few minutes after traumatic brain injury. The time course for this barrier disruption is characterized by three different patterns: (1) transient, (2) prolonged, and (3) delayed opening. This variation in the development of barrier disruption may be related to the secondary barrier failure as well as the primary opening after injury.
Animals↗
Hepatitis C virus RNA and long-term response to recombinant interferon-alpha 2b in patients with chronic hepatitis C.
The effectiveness of recombinant interferon-alpha 2b (rIFN-alpha 2b) in eradicating hepatitis C virus (HCV) RNA from serum has not been completely assessed. We studied 39 patients with compensated chronic hepatitis C diagnosed by liver biopsy and positive HCV RNA measured by polymerase chain reaction (PCR). Group I consisted of 26 patients treated with 3 MU of rIFN-alpha 2b for 6 months; group II, 13 control patients observed for six months; and group III, 12 out of 13 patients from group II who subsequently received 5 MU of rIFN-alpha 2b for 6 months. In group I, 11 out of 23 (47.8%) patients who completed treatment had an immediate response and five (21.7%) had a sustained response to therapy six months after treatment. No response was observed in patients from group II. In group III, 7 out of 12 (58.3%) patients who completed treatment had an immediate response and none had a sustained response. Considering all patients who completed rIFN-alpha 2b treatment, HCV RNA remained positive at the end of therapy in three of five sustained responders (60%), six of 13 patients who relapsed (46.1%), and in all nonresponders (100%). HCV RNA was positive 6 months after therapy in four (80%), 13 (100%), and 17 (100%) patients respectively. All patients with a sustained response had normal aminotransferase levels 18 months after therapy. We conclude that in chronic hepatitis C rIFN-alpha 2b causes a significant immediate response but this is not sustained, only 2.8% of treated patients had a sustained loss of HCV RNA. Normal aminotransferase persist in the long term, despite persistence of HCV RNA.
Adult↗
Molecular cloning of the gene which encodes beta-N-acetylglucosaminidase from a marine bacterium, Alteromonas sp. strain O-7.
The gene encoding the periplasmic beta-N-acetylglucosaminidase (GlcNAcase B) from a marine Alteromonas sp. strain, O-7, was cloned and sequenced. The protein sequence of GlcNAcase B revealed a highly significant homology with Vibrio GlcNAcase and alpha- and beta-chains of human beta-hexosaminidase.
Acetylglucosaminidase↗
[The effects of mild hypothermia on expression of stress protein (HSP72) after experimental brain injury].
Recent studies have demonstrated that mild hypothermia protects brain from ischemic insults. In the present study, we investigated the effects of mild hypothermia on stress responses of the neurons and glia after experimental brain injury. We evaluated the immunocytochemical expression of 72kDa molecular weight heat shock protein (HSP72) as a marker of cellular injury. Adult male Sprague-Dawley rats were subjected to a lateral fluid percussive injury. After injury the animals were divided into two groups (normothermic and hypothermic groups). Body temperature of the normothermic groups was maintained at 37.0-37.5 degrees C throughout the experiment. In the latter groups, the rats were exposed to hypothermia of 30.0-31.5 degrees C by surface cooling for 150 minutes beginning at 15 minutes after injury. Animals in each groups were sacrificed at 24, 48, and 72 hours after injury. Vibratomed brain sections were provided for immunocytochemical staining of HSP72 and hematoxyline-eosin staining. The induction of HSP72 was evaluated under the light microscopic level. Results 1) The rats that produced HSP72 in the hypothermic group were significantly less than those in the normothermic group. 2) HSP72 was expressed in the neurons and glia in the various brain regions including the impact site, parasagittal cortex, deep cortical layer, hippocampus, caudate-putamen and midbrain in both groups. However HSP72 positive cells in each brain region of the hypothermic group were significantly less than those in the corresponding regions of the normothermic group.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Gene sequence, purification and characterization of N-acetyl-beta-glucosaminidase from a marine bacterium, Alteromonas sp. strain O-7.
The gene (cht60) encoding N-acetyl-beta-glucosaminidase (Cht; EC 3.2.1.30) from the marine bacterium Alteromonas sp. strain O-7 was cloned into pUC18 in Escherichia coli JM109. The nucleotide (nt) sequence of cht60 was determined. A 1797-bp open reading frame encoded a polypeptide of 598 amino acids (aa) (M(r) 64,535). The aa sequence of the cloned enzyme (Cht60) deduced from the nt sequence showed no significant sequence homologies with available aa sequences from databases. Cht60 was purified from the periplasmic fraction of E. coli cells carrying pCHT982. The enzyme was most active towards p-nitrophenyl-N-acetyl-beta-D-glucosaminide(PNP-beta-GlcNAc) and diacetylchitobiose. The optimum pH and temperature of the enzyme were pH 7.5 and 37 degrees C, respectively. The N-terminal 11 aa residues of Cht60 were sequenced, and the location of the signal peptide cleavage site was clarified.
Acetylglucosaminidase↗
Immunocytochemical localization of immunoglobulins in the rat brain: relationship to the blood-brain barrier.
The central nervous system has been traditionally regarded as an immunologically privileged area. This feature has been in part attributed to the blood-brain barrier, which provides a restrictive interface to circulating immunoglobulins (IgG). Recent kinetic studies suggest that the barrier to immune proteins is not absolute, but rather may be regulated by a specific transfer mechanism. In this study, we confirm the presence of IgG in the central nervous system by immunocytochemistry and demonstrate a close anatomical relationship between the distribution of this protein and the blood-brain barrier. IgG was immunolocalized in the normal rat brain by using monoclonal and polyclonal antibodies to IgG and its subclasses. On the basis of an initial evaluation, the most appropriate antibodies and dilutions were selected for subsequent analyses. In the first study, IgG and albumin were immunolocalized in adjacent sections. In the second study, horseradish peroxidase (HRP) was given intravenously prior to sacrifice, in order to examine artifacts related to perfusion fixation. The distribution of HRP and IgG was then examined in adjacent sections. In the third study, IgG was immunolocalized in sections of brain after mild traumatic head injury. A monoclonal antibody to IgG2a and a polyclonal antibody to IgG were selected on the basis of specificity and consistent, mutual localization. Distinct, patchy, perivascular staining, infrequently associated with labeled neurons, was noted throughout the brain. Electron microscopy confirmed the perivascular localization; IgG was localized along the basal lamina of microvasculature and within the adjacent parenchyma. Albumin and HRP did not exhibit a similar pattern of perivascular immunostaining. After head injury, prominent immunostaining for IgG was observed in the injured hemisphere. In summary, these data indicate that the normal rat brain contains IgG, which dramatically increases after head injury. The distinct perivascular distribution in the normal brain suggests local microvascular permeability. This permeability is selective for IgG, since albumin does not share a similar perivascular localization. The neuronal staining which is closely associated with perivascular label may reflect one intracellular route for extravasated IgG.
Albumins↗
Comparative study of three doses of interferon-alpha 2a in chronic active hepatitis B. The International Hepatitis Trial Group.
To determine the efficacy of interferon-alpha 2a in chronic active hepatitis B, 238 patients were randomly divided, into four groups: three groups received either 2.5 MIU m-2, 5.0 MIU m-2 or 10.0 MIU m-2, three times weekly by intramuscular injection for 12-24 weeks; and a control group received no treatment. Patients were followed for up to 12 months after treatment was discontinued. There was a statistically significant difference in response [clearance of hepatitis B e antigen (HBeAg) and hepatitis B viral DNA (HBV-DNA)] between treated and untreated patients (37 vs 13%) but no statistically significant difference was seen between treatment groups (33%, 34% and 43% for the 2.5, 5.0 and 10.0 MIU m-2 groups, respectively). A transient rise in transaminases (seroconversion hepatitis) was seen in responders, but levels returned to within the normal range after response to treatment. In patients responding to interferon therapy there was a significant reduction in the severity of the hepatitis. Interferon-alpha 2a was generally well tolerated with respect to vital signs and laboratory parameters.
Adolescent↗
[Breakdown of the blood-brain barrier and clearance of extravasated proteins after experimental brain injury].
It is well recognized that extravasation of circulating proteins is contributed to the formation of vasogenic brain edema after traumatic brain injury. However, clearance of the extravasated proteins from brain tissue remains unclear. In the present study we therefore identified the clearance procedure by evaluating extravascular localization of endogenous serum albumin and exogenous protein tracer, horseradish peroxidase (HRP), after experimental brain injury in rats. Adult male Wistar rats were subjected to a lateral fluid percussive injury. In study 1, HRP was given intravenously 10 minutes before sacrifice. Animals were sacrificed at 1, 2, 24, 72 hours and 7 days after injury in order to determine re-establishment of the blood-brain barrier. In study 2 extravascular accumulation of serum albumin and HRP given before impact was examined at 1, 6, 24, 72 hours and 7 days after injury to evaluate the clearance of these extravasated proteins. Localization of each protein was assessed in injured brain sections at the microscopic level. In study 1, breakdown of the blood-brain barrier was noted in various regions of the injured brain at 1 hour. This barrier disruption was restored in almost regions by 2 hours. Impact site, however, remained permeable upto 72 hours. In study 2, the distribution of extravasated proteins was similar between albumin and HRP at 1 hour post-injury. Pronounced extravasation of both proteins occurred in discrete regions through the injured brain. After 6 hours post-injury a differential accumulation was noted between albumin and HRP. The diffuse extracellular accumulation of albumin was most widespread at 24 hours and less intense at 72 hours.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Immunolocalization of heat shock protein after fluid percussive brain injury and relationship to breakdown of the blood-brain barrier.
We have previously developed a model of mild, lateral fluid percussive head injury in the rat and demonstrated that although this injury produced minimal hemorrhage, breakdown of the blood-brain barrier was a prominent feature. The relationship between posttraumatic blood-brain barrier disruption and cellular injury is unclear. In the present study we examined the distribution and time course of expression of the stress protein HSP72 after brain injury and compared these findings with the known pattern of breakdown of the blood-brain barrier after a similar injury. Rats were subjected to a lateral fluid percussive brain injury (4.8-5.2 atm, 20 ms) and killed at 1, 3, and 6 h and 1, 3, and 7 days after injury. HSP72-like immunoreactivity was evaluated in sections of brain at the light-microscopic level. The earliest expression of HSP72 occurred at 3 h postinjury and was restricted to neurons and glia in the cortex surrounding a necrotic area at the impact site. By 6 h, light immunostaining was also noted in the pia-arachnoid adjacent to the impact site and in certain blood vessels that coursed through the area of necrosis. Maximal immunostaining was observed by 24 h postinjury, and was primarily associated with the cortex immediately adjacent to the region of necrosis at the impact site. This region consisted of darkly immunostained neurons, glia, and blood vessels. Immunostaining within the region of necrosis was restricted to blood vessels. HSP72-like immunoreactivity was also noted in a limited number of neurons and glia in other brain regions, including the parasagittal cortex, deep cortical layer VI, and CA3 in the posterior hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Cloning, sequence, and expression of a chitinase gene from a marine bacterium, Altermonas sp. strain O-7.
The gene encoding an extracellular chitinase from marine Alteromonas sp. strain O-7 was cloned in Escherichia coli JM109 by using pUC18. The chitinase produced was not secreted into the growth medium but accumulated in the periplasmic space. A chitinase-positive clone of E. coli produced two chitinases with different molecular weights from a single chitinase gene. These proteins showed almost the same enzymatic properties as the native chitinase of Alteromonas sp. strain O-7. The N-terminal sequences of the two enzymes were identical. The nucleotide sequence of the 3,394-bp SphI-HindIII fragment that included the chitinase gene was determined. A single open reading frame was found to encode a protein consisting of 820 amino acids with a molecular weight of 87,341. A putative ribosome-binding site, promoter, and signal sequence were identified. The deduced amino acid sequence of the cloned chitinase showed sequence homology with chitinases A (33.4%) and B (15.3%) from Serratia marcescens. Regardless of origin, the enzymes of the two bacteria isolated from marine and terrestrial environments had high homology, suggesting that these organisms evolved from a common ancestor.
Amino Acid Sequence↗
A controlled trial of high dose interferon, alone and after prednisone withdrawal, in the treatment of chronic hepatitis B: long term follow up.
This study was designed to evaluate the safety and effectiveness of high dose interferon, with or without prednisone pretreatment, in patients with chronic hepatitis B. Patients were randomised to two treatment groups: group I (n = 26) received six weeks of prednisone followed by a two week, drug free period, and then 10 million units (MU) of interferon alfa-2b three times weekly subcutaneously for 16 weeks; group II (n = 24) were used as controls for 24 weeks and then treated with interferon. Loss of hepatitis B e antigen (HBeAg) and hepatitis B virus (HBV)-DNA, with a return to normal alanine aminotransferase (ALT) activity, was seen in 16 of 26 group I patients (61.5%), in one group II patient (4.2%) during the control phase, and in 13 of 23 group II patients (56.5%) after interferon. Three of 26 (11.5%) in group I and one of 23 (4.3%) in group II eliminated the surface antigen (HBsAg). There were no statistically significant differences in response between groups I and II. Liver biopsies carried out in 20 patients showed that responders had a noticeable reduction in inflammation and disappearance of core antigen in liver tissue, changes not seen in non-responders. On long term follow up (four years), nine out of 28 responders (32.1%) eliminated HBsAg, and four initial non-responders had a late seroconversion.
Alanine Transaminase↗
Propranolol compared with propranolol plus isosorbide dinitrate in portal-hypertensive patients: long-term hemodynamic and renal effects.
The long-term hemodynamic and renal effects of propranolol were compared with those of propranolol plus isosorbide dinitrate in 44 portal-hypertensive alcoholic cirrhotic patients. Eight control patients, 8 patients receiving propranolol and 14 patients receiving propranolol plus isosorbide dinitrate were hemodynamically evaluated. Renal function was studied in a fourth group of 14 patients receiving propranolol plus isosorbide dinitrate. Portal pressure decreased more (p < 0.05) with combined therapy (-21.6%, from 19.5 +/- 4.8 to 15.4 +/- 4.3 mm Hg) than with propranolol alone (-12.5%, from 19.9 +/- 1.2 to 17.4 +/- 1.8 mm Hg). Serum urea and creatinine levels, plasma sodium concentration, urine volume and urinary sodium excretion showed nonsignificant changes in all groups studied. Combined therapy induced a significant (p < 0.05) decrease in plasma renin activity (from 4.42 +/- 4.7 to 1.59 +/- 1.9 ng/ml/hr) and nonsignificant reductions in plasma aldosterone concentration and creatinine clearance. None of the eight patients with ascites or history of ascites not receiving isosorbide dinitrate showed evidence of impairment in renal sodium metabolism during the study period. In contrast, 8 of the 14 patients (57%) with ascites or history of ascites receiving isosorbide dinitrate showed impairment in renal sodium metabolism (p < 0.01), as reflected by the development or worsening of ascites and the need of higher diuretic requirements. Long-term combined administration of propranolol plus isosorbide dinitrate is superior to propranolol alone in the pharmacological treatment of portal hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)
Blood Pressure↗
Breakdown of the blood-brain barrier after fluid percussive brain injury in the rat. Part 1: Distribution and time course of protein extravasation.
Experimental brain injury is associated with marked vasogenic edema, as evidenced by an increase in brain water content. This prominent and widespread response raises questions about the vulnerability of microvasculature in the brain to injury. In the present report we further characterize the vascular response by evaluating the integrity of the blood-brain barrier to circulating proteins. Vascular permeability to endogenous immunoglobulins (IgG) and to the protein horseradish peroxidase (HRP) was examined after a lateral, fluid percussive brain injury in the rat. In study 1 IgG was immunolocalized in brain sections 1-24 hr after injury. In studies 2 and 3 HRP was given intravenously either before impact (study 2) or 10 min before sacrifice (study 3). Permeability to this protein was assessed at 1-6 hr (study 2) or at 1-72 hr (study 3) after injury. In studies 1 and 2 the extravascular accumulation of proteins was evaluated. Pronounced abnormal permeability to IgG and HRP occurred within the first hour after injury and was widespread throughout both hemispheres. The intensity of immunostaining for IgG increased with time up to 24 hr after injury. In contrast, maximal extravascular accumulation of HRP occurred within the first hour after injury. In study 3 the time course for re-establishment of the blood-brain barrier to HRP was determined. Maximal permeability occurred at 1 hr after injury. At 24 hr abnormal permeability was restricted to the impact site and this area remained permeable up to 72 hr after injury. In summary this study demonstrates that breakdown of the blood-brain barrier to plasma proteins is a prominent feature of experimental brain injury. This abnormal permeability is characterized by its transient expression and widespread distribution. The time course for re-establishment of the blood-brain barrier to circulating proteins is most delayed at the impact site.
Animals↗