Prolonged neutropenia due to antihuman neutrophil antigen 2 (CD177) antibody after bone marrow transplantation

We describe a patient who presented with prolonged neutropenia due to anti‐human neutrophil antigen (HNA)‐2 (CD177) antibody after allogeneic bone marrow transplantation. A granulocyte immunofluorescence test showed bimodal expression of antineutrophil antibody that resulted from specific binding of anti‐HNA‐2 to CD177⁺ neutrophils from healthy donors. The patient did not respond to granulocyte colony stimulating factor, which is able to upregulate CD177 expression on neutrophils. The low percentage of CD177⁺ cells in the few remaining neutrophils supports the possibility of elimination of CD177‐upregulated neutrophils. These findings might explain an inferior response to neutrophil growth factors in neutropenia secondary to anti‐HNA‐2 antibody.     

Modifying Effects of Various Chemicals on Preneoplastic and Neoplastic Lesion Development in a Wide-spectrum Organ Carcinogenesis Model Using F344 Rats

Modifying potentials of various chemicals on tumor development were investigated in a wide-spectrum organ carcinogenesis model using male F344/DuCrj rats. The animals were treated with N-nitroso-diethylamine (100 mg/kg body weight, ip, single injection at the commencement of the study), N-methyl-N-nitrosourea (20 mg/kg body weight, ip, 4 times during weeks 1 and 2) and N-bis(2-hydroxypropyl)nitrosamine (0.1% in drinking water, during weeks 3 and 4) for multi-organ initiation and then were given one of 14 test chemicals including 6 hepatocarcinogens, 7 non-hepatocarcinogens and 1 non-carcinogen, or basal diet for 16 weeks. All rats were killed at the end of week 20, and the major organs were carefully examined for preneoplastic and neoplastic lesions. Immunohistochemical demonstration of glutathione S -transferase-positivc foci was also used for quantitative assessment of liver preneoplastic lesion development. Modifying effects were shown for 11 out of 14 test agents in the liver, forestomach, glandular stomach, lung, urinary bladder or thyroid, 7 of them targeting more than two organs. This was the first demonstration to our knowledge that cloflbrate possesses enhancing potential for urinary bladder carcinogenesis and an inhibiting effect on thyroid carcinogenesis. Caprolactam showed no effect in any organ, in agreement with its established inactivity. The results indicated that the system could be reliably applied as a medium-term multiple organ bioassay for assessment of the modification potential of test agents in unknown target sites.     

Spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia with specific RAS mutations

Of 11 children with juvenile myelomonocytic leukemia (JMML) carrying RAS mutations (8 with NRAS mutations, 3 with KRAS2 mutations), 5 had a profound elevation in either or both the white blood cells and spleen size at diagnosis. Three patients had no or modest hepatosplenomegaly and mild leukocytosis at presentation but subsequently showed a marked increase in spleen size with or without hematologic exacerbation, for which nonintensive chemotherapy was initiated. The other three patients with NRAS or KRAS2 glycine to serine substitution received no chemotherapy, but hematologic improvement has been observed during a 2- to 4-year follow up. In the third group, all hematopoietic cell lineages analyzed had the RAS mutations at the time of hematologic improvement, whereas DNA obtained from the nails had the wild type. Additionally, numbers of circulating granulocyte-macrophage progenitors were significantly reduced during the clinical course. Thus, some patients with JMML with specific RAS mutations may have spontaneously improving disease.     

Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia

Recently, somatic mutations of the nucleophosmin gene (NPM1), which alter the subcellular localization of the product, have been reported in acute myeloid leukemia (AML). We analyzed the clinical significance of NPM1 mutations in comparison with cytogenetics, FLT3, NRAS, and TP53 mutations, and a partial tandem duplication of the MLL gene (MLL-TD) in 257 patients with AML. We found NPM1 mutations, including 4 novel sequence variants, in 64 of 257 (24.9%) patients. NPM1 mutations were associated with normal karyotype and with internal tandem duplication (ITD) and D835 mutations in FLT3, but not with other mutations. In 190 patients without the M3 French-American-British (FAB) subtype who were treated with the protocol of the Japan Adult Leukemia Study Group, multivariate analyses showed that the NPM1 mutation was a favorable factor for achieving complete remission but was associated with a high relapse rate. Sequential analysis using 39 paired samples obtained at diagnosis and relapse showed that NPM1 mutations were lost at relapse in 2 of the 17 patients who had NPM1 mutations at diagnosis. These results suggest that the NPM1 mutation is not necessarily an early event during leukemogenesis or that leukemia clones with NPM1 mutations are sensitive to chemotherapy.     

3‐[(2,4‐dimethoxy)benzylidene]‐anabaseine dihydrochloride protects against 6‐hydroxydopamine‐induced parkinsonian neurodegeneration through α7 nicotinic acetylcholine receptor stimulation in rats

To explore a novel therapy against Parkinson's disease through enhancement of α7 nicotinic acetylcholine receptor (nAChR), we evaluated the neuroprotective effects of 3‐[(2,4‐dimethoxy)benzylidene]‐anabaseine dihydrochloride (DMXBA; GTS‐21), a functionally selective α7 nAChR agonist, in a rat 6‐hydroxydopamine (6‐OHDA)‐induced hemiparkinsonian model. Microinjection of 6‐OHDA into the nigrostriatal pathway of rats destroys dopaminergic neurons selectively. DMXBA dose dependently inhibited methamphetamine‐stimulated rotational behavior and dopaminergic neuronal loss induced by 6‐OHDA. The protective effects were abolished by methyllycaconitine citrate salt hydrate, an α7 nAChR antagonist. Immunohistochemical study confirmed abundant α7 nAChR expression in the cytoplasm of dopaminergic neurons. These results indicate that DMXBA prevented 6‐OHDA‐induced dopaminergic neuronal loss through stimulating α7 nAChR in dopaminergic neurons. Injection of 6‐OHDA elevated immunoreactivities to glial markers such as ionized calcium binding adaptor molecule 1, CD68, and glial fibrillary acidic protein in the substantia nigra pars compacta of rats. In contrast, these immunoreactivities were markedly inhibited by comicroinjection of DMXBA. Microglia also expressed α7 nAChR in both resting and activated states. Hence, we hypothesize that DMXBA simultaneously affects microglia and dopaminergic neurons and that both actions lead to dopaminergic neuroprotection. The findings that DMXBA attenuates 6‐OHDA‐induced dopaminergic neurodegeneration and glial activation in a rat model of Parkinson's disease raisethe possibility that DMXBA could be a novel therapeutic compound to prevent Parkinson's disease development. © 2012 Wiley Periodicals, Inc.     

Results of surgical treatments of primary hepatocellular carcinoma: Some aspects to improve long-term survival

From 1973 through 1982 we have treated 226 patients with primary hepatocellular carcinoma, including 103 by hepatectomy and 93 by hepatic artery ligation. Most were associated with cirrhosis or related liver diseases and one-third with esophageal varices. As in other Japanese and Asian series, our long-term overall results for the 90 patients who survived hepatectomy were poor in comparison with Western series dealing with non-cirrhotic patients. However, the actuarial survival rate at 3 years was 90% in patients with carcinomas smaller than 3 cm in diameter (n = 18). The 5-year survival rate was 70.8% in the 25 patients whose carcinoma had a curative resection, and 100% at 3 years in the 16 patients in whom a tumor smaller than 5 cm had been resected. Eighty-four patients survived hepatic artery ligation; in 50 of them the area of ischemia was thought to include all the neoplastic lesions within the liver. The survival rate of these 50 patients was superior to that of the patients who had undergone noncurative hepatic resection. We conclude that early detection and curative resection is the best way to improve the long-term results in cirrhotic patients with hepatocellular carcinoma and that hepatic artery ligation is better than incomplete (noncurative) resection.

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Resumen Hemos tratado 226 pacientes con carcinoma hepatocelular primario entre 1973 y 1982, incluyendo 103 con hepatectomía y 93 con ligadura de la arteria hepática. La mayoría apareció asociada con cirrosis o enfermedades hepáticas relacionadas y un tercio con varices esofágicas. Al igual que en otras series japonesas y asiáticas, nuestros resultados globales a largo término para los 90 pacientes que sobrevivieron la hepatectomía fueron pobres en comparación con las series occidentales que incluyen pacientes no cirróticos. Sin embargo, la tasa de supervivencia actuarial a 3 años fue del 90% en pacientes con carcinomas menores de 3 cm de diámetro (n= 18). La tasa de supervivencia en 5 años fue de 70,8% en los 25 pacientes cuyos carcinomas fueron sometidos a resección curativa, y del 100% en 3 años en los 16 pacientes en quienes se resecó un tumor de menos de 5 cm de diámetro. Ochenta y cuatro pacientes sobrevivieron la ligadura de la arteria hepática; en 50 de éstos se consideró que el área de isquemia incluía las lesiones neoplásicas contenidas en el hígado. La tasa de supervivencia de estos 50 pacientes fue superior a la de los pacientes que fueron sometidos a resección hepática no curativa.Nuestra conclusión es que la detección precoz y la resección curativa son la mejor manera de superar los resultados a largo plazo en pacientes cirróticos con carcinoma hepatocelular y que la ligadura de la arteria hepática es superior a la resección incompleta (no curativa).

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Résumé De 1973 à 1982 les auteurs ont opéré 226 malades qui présentaient un cancer hépatocellulaire, 103 par hépatectomie et 93 par ligature de l'artère hépatique. La majorité des patients présentaient une cirrhose ou des lésions hépatiques, un tiers étaient porteurs de varices oesophagiennes. Comme dans les autres séries japonaises ou asiatiques, les résultats à long terme chez les 90 malades qui avaient subi une hépatectomie furent décevants par comparaison avec les séries occidentales concernant les sujets indemnes de cirrhose. Cependant la survie actuarielle à 3 ans fut de 90% chez les opérés qui présentaient un cancer d'un diamètre inférieur à 3 cm (n=18). Le taux de survie à 5 ans fut de 70,8% chez 25 malades qui avaient subi une résection à but curatif, et le taux de survie à 3 ans fut de 100% chez 16 opérés qui avaient subi une résection pour une tumeur d'un diamètre inférieur à 5 cm. Quatrevingt-quatre malades ont survécu à la ligature de l'artère hépatique; chez 50 d'entre eux la zone ischémique provoquée par la ligature intéressait la totalité de la région hépatique occupée par les lésions néoplasiques. Le taux de survie de ces 50 malades fut toujours supérieur à celui de ceux qui n'avaient pu être l'objet d'une résection hépatique.De cette étude, on peut retenir les conclusions suivantes: le diagnostic précoce et la résection à but curatif du cancer hépatocellulaire chez les cirrhotiques représentent des conditions favorables à l'obtention de résultats à long terme satisfaisants; les résultats de la ligature de l'artère hépatique sont supérieurs à ceux de la résection incomplète (résection à but non curatif).

     

MAGE-D1 regulates expression of depression-like behavior through serotonin transporter ubiquitylation

The ubiquitin-proteasome system (UPS) controls the stability of most cellular proteins. The polymorphism of UPS-related genes is associated with major depression disorder, but less is known about the molecule that plays a role in depression by modulating the UPS. Melanoma antigen gene-D1 (MAGE-D1) interacts with RING E3 ubiquitin ligase and is implicated in protein degradation. MAGE-D1 may thus play an important role in the CNS via ubiquitylation. Here, we clarified a novel role of MAGE-D1 in emotional functions, namely its modulation of ubiquitylation to the serotonin transporter (SERT). The MAGE-D1 knock-out and knockdown by small interfering RNA (siRNA) in the prefrontal cortex showed depression-like behavior, such as a decrease in exploratory behavior in both the home cage and novel apparatus, a decrease in social interaction, increased immobility time during forced swimming and tail suspension, and a decrease in sucrose preference without any anxiety, or cognitive or motor dysfunction. Acute and chronic (28 d) administration of sertraline (10 mg/kg) and imipramine (20 mg/kg) reversed all or part of depression-like behavior in knock-out mice. In these mice, the serotonergic function in the prefrontal cortex and hippocampus was hypoactive, accompanied by hyperexpression of SERT attributable to a decrease in ubiquitylation. Furthermore, MAGE-D1 binds to SERT via the necdin homology domain. MAGE-D1 overexpression in cells resulted in a decrease in serotonin uptake activity and the protein level of SERT but an increase in ubiquitylated SERT. Together, the present findings suggest a novel role for MAGE-D1 in depressive behaviors: modulating SERT ubiquitylation.     

Quadro-pulse stimulation is more effective than paired-pulse stimulation for plasticity induction of the human motor cortex

OBJECTIVE: Repetitive paired-pulse transcranial magnetic stimulation (TMS) at I-wave periodicity has been shown to induce a motor-evoked potential (MEP) facilitation. We hypothesized that a greater enhancement of motor cortical excitability is provoked by increasing the number of pulses per train beyond those by paired-pulse stimulation (PPS). METHODS: We explored motor cortical excitability changes induced by repetitive application of trains of four monophasic magnetic pulses (quadro-pulse stimulation: QPS) at 1.5-ms intervals, repeated every 5s over the motor cortex projecting to the hand muscles. The aftereffects of QPS were evaluated with MEPs to a single-pulse TMS, motor threshold (MT), and responses to brain-stem stimulation. These effects were compared to those after PPS. To evaluate the QPS safety, we also studied the spread of excitation and after discharge using surface electromyograms (EMGs) of hand and arm muscles. RESULTS: Sizes of MEPs from the hand muscle were enhanced for longer than 75min after QPS; they reverted to the baseline at 90min. Responses to brain-stem stimulation from the hand muscle and cortical MEPs from the forearm muscle were unchanged after QPS over the hand motor area. MT was unaffected by QPS. No spreads of excitation were detected after QPS. The appearance rate of after discharges during QPS was not different from that during sham stimulation. CONCLUSIONS: Results show that QPS can safely induce long-lasting, topographically specific enhancement of motor cortical excitability. SIGNIFICANCE: QPS is more effective than PPS for inducing motor cortical plasticity.     

Deep vein thrombosis in the psychiatric patients under physical restraint]

Pulmonary thromboembolism induced by deep vein thrombosis (DVT), which is known as economy-class syndrome, is one of sudden death in psychiatric patients under physical restraint. (1) A decrease in venous blood flow, (2) damage to vessel walls, and (3) the enhancement of blood clotting are the major risk factors for DVT (Virchow triad). It has been speculated that physical restraint inhibits venous blood flow, and that antipsychotic drugs facilitate blood clotting. In order to prevent sudden death due to DVT, prophylactic measures and early diagnosis are crucial. Whereas Doppler ultrasonography and contrast venography are the gold standards for the diagnosis of DVT, more simplified methods are now under development. Of those, D-dimer measurement, which can be conducted with a small blood sample, is the most potent candidate for the biochemical diagnosis of DVT. Although there are many prophylactic measures, including anticoagulant medications and physical therapies, it is not clear which is the most effective and suitable in psychiatric practice. Psychiatric professionals should pay closer attention to DVT in psychiatric patients under physical restraint.