Acute heart failure syndromes and coronary perfusion.

Acute heart failure syndromes (AHFS), with a high post-discharge mortality and rehospitalization rate, represent a significant public health burden. The treatment of patients hospitalized with AHFS often includes the use of vasoactive medications such as inotropes and vasodilators. Although such agents are frequently used, their safety and efficacy remain controversial. A significant number of patients with heart failure have underlying coronary artery disease and may be at greater risk from hemodynamic alterations that can diminish coronary perfusion. In AHFS, the relationship among vasoactive medications, coronary perfusion, and potential myocardial injury needs further investigation. Newer techniques now available to evaluate coronary perfusion should provide guidance for the evaluation of existing and future vasoactive therapies for AHFS.

Contrast media: procedural capacities and potential risks.

Contrast media are known to have transient hemodynamic properties that can influence a patient's clinical status, including heart rate variability and blood pressure. These changes have the potential to impact the diagnostic quality of CT scans. Although most patients are able to receive contrast media without significant adverse reactions, events occur in a minority of cases. These reactions range from mild discomfort (injection-associated pain and heat sensation) to more significant cardiac, renal, and hypersensitivity reactions. The incidence of adverse reactions varies with the type of contrast media used, and several randomized trials have elucidated the cardiac and renal differences among agents. Risk factors for contrast-induced acute kidney injury (CIAKI) have been established, with baseline kidney disease amplified by the presence of diabetes constituting the highest-risk patient group. Strategies for preventing CIAKI include antioxidant therapy, hydration regimens, and choice of contrast agents. Enhanced knowledge on the part of physicians and medical personnel regarding the properties and potential side effects of iodinated contrast agents should lead to improved patient safety and efficacy when performing radiologic examinations.

Activation of mitogen-activated protein kinases in experimental cerebral ischemia.

OBJECTIVES: Mitogen-activated protein kinases (MAPK) regulate cell survival and differentiation. The aim of the present study is to investigate the activation pattern of different MAPKs [extracellular signal-regulated kinase (ERK), c-jun-N-terminal kinase (JNK) and p38] after cerebral ischemia. MATERIAL AND METHODS: Rats were subjected to cerebral ischemia using a model for transient (2 h) and permanent middle cerebral artery occlusion (MCAO). The rats were allowed 6 h to 1 week of survival before immunohistochemical evaluation with phospho-specific antibodies, recognizing activated MAPKs. RESULTS: ERK was activated in ipsilateral blood vessels, neurons and glia, but also in contralateral vessels. JNK activation was absent in neurons but appeared in arterial blood vessels and glia at the lesion side. Active p38 was observed in macrophages in maturing infarcts. CONCLUSIONS: ERK and JNK may participate in the angiogenic response to cerebral ischemia. ERK, but not JNK, was activated in neurons, possibly indicating a pathophysiologic role. Active p38 might be involved in the inflammatory reaction.

Abordaje laparoscópico del hiato previamente operado / Laparoscopic reoperative hiatal surgery

Introducción. La cirugía del hiato esofágico se ha convertido en una de las mejores indicaciones para el abordaje laparoscópico. Sin embargo, se ha evidenciado una mayor incidencia de recidivas precoces que precisan ser reintervenidas, y se ha propuesto que las reintervenciones sobre el hiato previamente operado pueden ser factibles mediante abordaje laparoscópico manteniendo las ventajas de un abordaje mínimamente invasivo. Objetivo. Evaluar los resultados inmediatos del abordaje laparoscópico del hiato operado previamente. Material y métodos. Entre enero de 1998 y septiembre de 2001 se han efectuado 126 intervenciones sobre el hiato esófagico (101 por reflujo y/o hernia hiatal y 25 por acalasia). De ellos, 7 pacientes habían sido previamente intervenidos. Se ha analizado edad, tipo de cirugía previa, estancia, conversión y morbilidad. Resultados. Esta serie incluye 3 varones y 4 mujeres. Cinco de ellos habían sido intervenidos de forma abierta (tres por hernia de hiato, uno por acalasia y otro por úlcera duodenal perforada) y dos pacientes habían sido intervenidas de forma laparoscópica por hernia de hiato. En seis de los siete pacientes (86 por ciento) la reintervención se completó por laparoscopia, con un tiempo quirúrgico medio de 230 min (límites, 180-300). Se efectuaron 4 funduplicaturas de Nissen y una ampliación de la miotomía más funduplicatura tipo Dor. La estancia media fue de 3,5 días, sin complicaciones y los pacientes permanecen asintomáticos tras un seguimiento de 9,8 meses (límites, 4-17 meses). Conclusiones. Las reintervenciones laparoscópicas del hiato esofágico son factibles y a la vez se acompañan de una evolución similar a las intervenciones laparoscópicas convencionales (AU)

Good prognosis of patients with acute promyelocytic leukemia who achieved second complete remission (CR) with a new retinoid, Am80, after relapse from CR induced by all-trans-retinoic acid.

A new synthetic retinoid, Am80, is effective in treating acute promyelocytic leukemia relapsed from all-trans-retinoic acid-induced complete remission (CR). We report here the long-term clinical outcomes of patients who achieved second CR with Am80. Of 24 evaluable patients, 14 achieved a second CR by Am80 therapy. Of those patients, 4 relapsed within 6 months, despite subsequent consolidation chemotherapy. Six patients underwent sibling or unrelated HLA-matched allogeneic bone marrow transplantation (BMT), and 4 are alive without relase for more than 49 months after achieving second CR. Four of 8 patients who did not receive BMT are alive without relapse for more than 49 months. Promyelocytic leukemia-retinoic acid receptor alpha (PML-RAR alpha) fusion transcript was undetectable by reverse transcriptase-polymerase chain reaction in all living patients. Therefore, if patients achieve second CR with Am80 and HLA-matched donors are available, BMT is the treatment of choice. However, it is noteworthy that CR was maintained for more than 49 months in half of the patients who did not receive BMT.

Expression of transforming growth factor-beta1, 2, 3 isoforms and type I and II receptors in acute focal cerebral ischemia: an immunohistochemical study in rat after transient and permanent occlusion of middle cerebral artery.

Transforming growth factor beta (TGF-beta) is involved in the modulation of cell growth, differentiation and repair following injury of various organs. Previous studies on human autopsy material have indicated that TGF-beta isoforms-beta1, -beta2 and -beta3, and TGF-beta receptor type I are expressed in various cells of necrotizing brain lesions like infarction and abscess. The present immunohistochemical study was designed to investigate changes that may occur with regard to TGF-beta and its receptors type I and II in a rat model of focal brain ischemia induced by transient or permanent occlusion of the middle cerebral artery. Our findings indicate that at days 1 and 3 following such transient and permanent ischemia there is an up-regulation of TGF-beta isoforms -beta1, -beta2 and -beta3, and TGF-beta receptor types I and II mainly in the perifocal neurons, reactive astroglial cells, endothelial cells and macrophages.

Expression of vascular endothelial growth factor (VEGF) and its receptors (Flt-1 and Flk-1) following permanent and transient occlusion of the middle cerebral artery in the rat.

Vascular endothelial growth factor (VEGF) is a known endothelial mitogen and a potent enhancer of vascular permeability although its role in focal cerebral ischemia is still not completely understood. The present report describes the immunohistochemical distribution of VEGF and its 2 receptors, Flt-1 and Flk-1 at day 1 and 3 following permanent and transient middle cerebral artery occlusion (MCAO) in the rat. A bilateral increase in VEGF immunoreactivity, particularly in neurons and blood vessels, was seen in both the experimental designs by day 1. By day 3, the immunoreactivity was restricted chiefly to the lesion side, where reaction was most prominent in the border zones of the infarcts. Immunoreaction to VEGF was more pronounced in cases of permanent MCAO than in transient MCAO. Flt-1 reaction was increased in neurons, glial and endothelial cells after both transient and permanent MCAO. Immunoreactivity to Flk-1 was prominent in glial cells and was present to some extent in endothelial cells. These findings indicate an early upregulation of VEGF and its receptors after permanent as well as transient focal cerebral ischemia in the rat.

[Concordant improvement of progressive systemic sclerosis and chronic myelogenous leukemia with interferon-alpha treatment].

A 44-year-old woman with progressive systemic sclerosis (PSS) visited our clinic because of leukocytosis and thrombocytosis. She was diagnosed as having chronic myelogenous leukemia (CML) with PSS, and was treated with interferon-alpha 2b (IFN-alpha) after pretreatment of hydroxyurea as a cytoreduction. Complete hematological remission was obtained two months later, and four months later minimal cytogenetic response was achieved by IFN-alpha. Her PSS symptoms were also improved to some extent as judged by Rodnan's total skin score, maximal opening distance of oral cavity, and range of motion of wrists. Our results suggest that IFN-alpha is probably beneficial not only for CML itself but also for PSS, too.

Red cell membrane disorders in the Japanese population: clinical, biochemical, electron microscopic, and genetic studies.

Based on studies on 610 cases of hereditary red cell membrane disorders, the characteristic features of the incidence of these disorders in the Japanese population are described. These patients were screened by a protocol on red cell morphology (scanning electron microscopy), on red cell membrane proteins (sodium dodecylsulfate polyacrylamide gel electrophoresis, and kinetics of membrane proteins), biophysical studies (ektacytometry, mechanical stability and fluorescence recovery after the photobleaching method), membrane transport (sodium influx and efflux, and anion transport), gene analysis (spectrins, band 4.2 and band 3), surface markers (blood type antigens and sialic acid content), and development and expression of membrane proteins (using a two-phase liquid culture system). Among the molecular abnormalities detected, alpha-spectrin mutation appeared rare (only one family with spectrin alpha I/74), as opposed to two beta-spectrin mutations in Japan out of seven worldwide cases. Two unrelated kindreds with a chromosomal abnormality; that is, del (8) (p11.2-p21.1), were found that involved the possible contribution of ankyrin to the pathogenesis of hereditary spherocytosis. Anomalies of a transmembrane domain of band 3 were detected in two independent kindreds with impaired anion transport. Among 16 HE patients, 13 cases were partially band 4.1 deficient. Complete band 4.2 deficiency of the Nippon type (GCT-->ACT at codon 142 in band 4.2 gene) was observed in 17 cases of 13 unrelated kindreds. Other forms of band 4.2 deficiency without the mutation were also detected in three kindreds. Band 7 deficiency was found in seven cases with hereditary stomatocytosis independent of the presence or absence of cation transport abnormalities. A relatively high incidence of hereditary high red cell membrane phosphatidylcholine hemolytic anemia was disclosed by the analysis of red cell membrane lipids.

Electron microscopic and physicobiochemical studies on disorganization of the cytoskeletal network and integral protein (band 3) in red cells of band 4.2 deficiency with a mutation (codon 142: GCT-->ACT).

The role of band 4.2 deficiency in the pathogenesis of red cell membrane dysfunctions was studied in seven unrelated patients with complete band 4.2 deficiency with a point mutation (142 GCT-->ACT; 142 Ala-->Thr) on the cDNA of the band 4.2 gene. Two major types of abnormalities were detected in these patients; (A) abnormalities of the cytoskeletal network in the horizontal dimension, and (B) abnormalities of band 3 in the vertical dimension. Electron microscopy by the surface replica method and the quick-freeze deep-etching method demonstrated the markedly impaired cytoskeletal network (a disorganized cobblestone pattern, uneven distribution of junctional units, and the appearance of bulky aggregates after heat treatment). Ektacytometry showed a markedly decreased red cell deformability especially at 48 degrees C, although the cytoskeletal proteins themselves were essentially normal with normal mechanical stability of the Triton-shells. Electron microscopy by the freeze fracture method revealed a decreased number and a random distribution of intramembrane particles (IMPs) with a shift of the IMPs to a larger size. Fluorescence recovery after photobleaching studies on band 3 indicated the marked increase of its mobile fraction. The extractability of band 3 by Triton X in vitro was markedly enhanced, although the physico-biochemical properties of band 3 itself (the cleavage pattern of band 3 fragments, and the binding properties of band 3 to band 4.2 or ankyrin) were basically normal. These findings demonstrate that band 4.2 plays a crucial role in the maintenance of the normal structure and functions of both the cytoskeletal and integral proteins (band 3).

A deletional frameshift mutation of the beta-spectrin gene associated with elliptocytosis in spectrin Tokyo (beta 220/216).

A novel spectrin variant carrying a truncated beta-chain and designated Spectrin Tokyo (beta 220/216) is presented. It was associated with elliptocytosis and moderate uncompensated hemolysis. The dimer self-association was reduced. An increase of the alpha I 74-Kd fragment was detected upon partial trypsin digestion. Analysis of cDNA and genomic DNA showed a 1-base deletion in codon 2059 (GCC AGC-->GCA GCT; Ala-Ser-->Ala-Ala) that belongs to exon X of spectrin beta-gene. A missense sequence extended down to (new) codon 2075. Serine 2060, a potential phosphorylation site, was replaced by alanine. The shortened beta-chain failed to undergo phosphorylation in vitro. Spectrin Tokyo shared the same stop codon, overlapping normal codons 2076 and 2077 (CTG AAA), as Spectrin Nice (beta 220/216), which is caused by a dinucleotide insertion in codon 2046 and contains 2076 amino acids. However, for some reason, Spectrin Tokyo had a lower incorporation level into the membrane than Spectrin Nice.

An alanine-to-threonine substitution in protein 4.2 cDNA is associated with a Japanese form of hereditary hemolytic anemia (protein 4.2NIPPON).

Erythrocyte (RBC) protein 4.2 (P4.2)-deficiency observed in Japanese individuals results in a hemolytic anemia associated with abnormally shaped (spherocytic, ovalocytic, and elliptocytic), osmotically fragile RBCs, the clinical presentation of which resembles hereditary spherocytosis (HS). By sodium dodecyl sulfate-polyacrylamide gel electrophoresis, P4.2-deficient individuals contain less than 1% of the normal membrane content of P4.2 and immunologic analysis shows that the P4.2 present exists as an equimolar doublet of 74-Kd and 72-Kd bands, in contrast to normal RBC membranes where a discrete 74-Kd band is not observed. RBC membranes from both of the biologic parents of a P4.2-deficient individual contained both the 74-Kd and the 72-Kd bands, demonstrating their heterozygosity for the P4.2 defect. The molecular basis of Japanese P4.2-deficiency was investigated by reverse transcription of total reticulocyte RNA, followed by polymerase chain reaction (PCR) amplification, subcloning, and sequencing. The complete cDNA sequence of a P4.2-deficient patient showed a single point mutation that changes codon 142 from GCT (alanine) to ACT (threonine) (Protein 4.2NIPPON). The mutation also eliminated an HgaI restriction site, therefore allowing rapid screening for the presence of the mutation. Screening of PCR-amplified genomic DNA showed that the mutation was present in the homozygous state in four (eight chromosomes) unrelated Japanese P4.2-deficient individuals and absent in 35 (70 chromosomes) P4.2-normal controls (including 15 Japanese [30 chromosomes]). The presence of the mutation was confirmed by allele-specific hybridization. The mutation occurred in an alternatively spliced exon that is present in two of four P4.2 mRNA splicing isoforms. These results demonstrate that Japanese P4.2-deficiency is closely associated with the P4.2 gene and does not arise secondarily to a defect in another membrane protein, and further suggest that the P4.2-deficiency is related to the pathogenesis of the hemolytic anemia in this variant form of recessively inherited spherocytosis.

[Abnormalities of beta spectrin with hereditary elliptocytosis in mother and child].

It is generally considered that abnormality of the erythrocyte membrane skeleton co elliptocytes. There are, however, few reports of beta spectrin variants. We found a new variant of beta spectrin in a child and her mother. This report is the first case of abnormality of beta spectrin in Japan. The propositus was an 8 month-old girl who was first examined by us in 1988. On laboratory findings, she showed anemia, increased reticulocyte count and decreased haptoglobin concentration. Both peripheral blood smears of patient and her mother showed typical elliptocytosis and they were diagnosed as hereditary elliptocytosis. SDS-PAGE patterns of the red cell membranes of the propositus and her mother were characterized by the presence of an abnormal component migrating immediately below the spectrin chains. We confirmed that the abnormal spectrin appeared clearly at the expense of normal beta chain. The abnormal spectrin (M.W. 216,000d) makes up 16% of the total beta chain. The inheritance of our case was autosomal dominant. The present case is considered as a new spectrin variant.

[Ectopic production of amylase by a non-producing type of multiple myeloma].

The patient was a 64-year-old woman who was admitted to our hospital because of lumbago. A diagnosis of multiple myeloma (non-producing type) was made, based on (1) the presence of multiple osteolytic lesions, (2) hypercellular marrow with 64.2% plasmacytoid malignant cells, (3) no monoclonal gamma-globulin was detected in the serum and urine, and (4) abnormal monoclonal gamma-globulin was also not detected in the cytoplasm and membranes of these malignant cells. After several courses of chemotherapy, a pleural effusion infiltrated by myeloma cells developed and the patient's serum contained a markedly increased amylase activity of salivary-type. Amylase activity was also detected in vitro in the supernatant of cultured myeloma cells established from the patient's pleural effusion. The presence of alpha-amylase in the myeloma cells, which were derived from pleural effusion, was demonstrated immuno-histochemically. These observations indicates that amylase was ectopically produced by these myeloma cells. Interestingly, 14 out of 20 metaphases in the cells derived from pleural effusion showed translocation of 1p22 near the region of 1p21, where the amylase gene was assigned.

[Hereditary stomatocytosis of the hydrocytosis type: a report of one family and red cell membrane studies].

A case of hereditary stomatocytosis with hemolytic anemia, increased autohemolysis, increased osmotic fragility, and shortened erythrocyte survival is reported. The erythrocytes were abnormally permeable to sodium and potassium; the sodium concentration of the erythrocytes was high, and the potassium level was low. This case was different from the first reported Japanese case of hereditary stomatocytosis of the hydrocytosis type in the Na(+)-K+ ATPase and Mg+ ATPase activity. In the first reported Japanese case, these activities were within normal limits, but in this case, they were increased. The findings indicate that membrane transport in hereditary stomatocytosis of the hydrocytosis type may vary from case to case.

Molecular characterization and nonradioactive detection of beta-thalassemia in Malaysia.

The spectrum of beta-thalassemia mutations in Malaysia has been determined in 45 beta-thalassemia chromosomes using dot blot hybridization of the polymerase chain reaction amplified DNA and direct DNA sequencing. Eleven different molecular defects, including those previously detected in Chinese, Asian Indians, and American blacks, and a novel frameshift mutation causing beta zero-thalassemia were detected. Since this novel mutation, a T deletion in codon 15 creates a new restriction site for EcoRII enzyme; the mutation could be detected by EcoRII digestion of the appropriate amplified fragment. The results of the present study provide additional information on the molecular heterogeneity of beta-thalassemia in this population. We also demonstrated the nonradioactive detection method of the beta-thalassemia mutation based upon the digoxigenin-labeled oligonucleotide probes.

Progressive dementia with motor neuron disease. An additional case report and neuropathological review of 20 cases in Japan.

A 68-year-old male had the characteristic clinical features of progressive dementia accompanied by motor neuron disease. The duration of his illness was 26 months. The chief findings from light microscopic studies were: diffue neuronal degeneration characterized by a simple atrophy and a mild disappearance of nerve cells throughout the CNS. Status spongiosus was observed in the basal ganglia. There were lesions similar to those of a motor neuron disease in the brain stem and spinal cord. Although there were no clinical symptoms of an extrapyramidal disease, severe involvement was seen in the substantia nigra. This patient belongs to the same group of cases of presenile dementia with motor neuron disease described by the author. A neuropathological review of 20 similar cases reported in Japan is discussed and the possibility of a new disease entity for these cases is suggested.