Chemotherapy after nivolumab for advanced gastric cancer (REVIVE): a prospective observational study.

BACKGROUND: Nivolumab therapy is a standard-of-care treatment for heavily pretreated patients with advanced gastric cancer (AGC). Previous studies have reported improvement in the objective response rate to chemotherapy after nivolumab therapy for other types of cancer. This study evaluated the efficacy and safety of chemotherapy after nivolumab therapy in AGC. PATIENTS AND METHODS: We conducted a prospective, multicenter, observational study in pretreated patients with nivolumab-refractory or -intolerant AGC. Patients received irinotecan, oxaliplatin-containing regimens, or trifluridine/tipiracil. The primary endpoint was overall survival. RESULTS: A total of 199 patients were included (median age: 69 years; male: 70%; female: 30%). Median overall survival and progression-free survival were 7.5 months [95% confidence interval (CI): 6.7-9.7 months] and 2.9 months (95% CI: 2.2-3.5 months), respectively. Objective response and disease control rates were 16.8% (95% CI: 11.6% to 23.6%) and 18.9% (95% CI: 38.9% to 54.6%), respectively. A prognostic index using alkaline phosphatase and the Glasgow Prognostic Score was generated to classify patients into three risk groups (good, moderate, and poor). The hazard ratios of the moderate and poor groups to the good group were 1.88 (95% CI: 1.22-2.92) and 3.29 (95% CI: 1.92-5.63), respectively. At the initiation of chemotherapy, 42 patients had experienced immune-related adverse events due to prior nivolumab therapy. The most common grade 3-4 adverse events were neutropenia (7.5%), anemia (8.0%), and anorexia (7.5%). CONCLUSIONS: The administration of cytotoxic chemotherapy after nivolumab therapy may give rise to a synergistic antitumor effect in AGC. Further investigation is warranted to confirm these findings.

Low-dose gonadotropin-releasing hormone agonist therapy (draw-back therapy) for successful long-term management of adenomyosis associated with cerebral venous and sinus thrombosis from low-dose oral contraceptive use.

The authors report a case of cerebral venous and sinus thrombosis (CVST) in a patient receiving a low-dose estrogen-progestin combination (oral contraceptives, OCs) for uterine adenomyosis. She was switched to gonadotropin-releasing hormone agonist (GnRHa) draw-back therapy, which was successfully administered long-term. CASE: The patient was a 38-year-old nulligravida with a history of smoking. She presented to this hospital with dysmenorrhea and postmenstrual lower abdominal pain. Adenomyosis was diagnosed using ultrasound and magnetic resonance imaging. She was instructed to stop smoking and was administered low-dose OCs. CVST occurred 18 months later. OC therapy was halted, and only antiplatelet therapy was administered. After six months, her chief complaint symptoms intensified, therefore GnRHa draw-back therapy was administered after obtaining informed consent. No uterine enlargement was observed, and the abdominal pain resolved. During 2.5 years of therapy, her bone density levels remained within normal limits. CVST did not recur and no other thromboses were observed.

Critical role of the neural pathway from the intermediate medial mesopallium to the intermediate hyperpallium apicale in filial imprinting of domestic chicks (Gallus gallus domesticus).

Filial imprinting in precocial birds is a useful model for studying early learning and cognitive development, as it is characterized by a well-defined sensitive or critical period. We recently showed that the thyroid hormone 3,5,3'-triiodothyronine (T3) determines the onset of the sensitive period. Moreover, exogenous injection of T3 into the intermediate medial mesopallium (IMM) region (analogous to the associative cortex in mammals) enables imprinting even on post-hatch day 4 or 6 when the sensitive period has been terminated. However, the neural mechanisms downstream from T3 action in the IMM region remain elusive. Here, we analyzed the functional involvement of the intermediate hyperpallium apicale (IMHA) in T3 action. Bilateral excitotoxic ablation of the IMHA prevented imprinting in newly hatched chicks, and also suppressed the recovery of the sensitive period by systemic intra-venous or localized intra-IMM injection of T3 in day-4 chicks. In contrast to the effect in the IMM, direct injection of T3 into the IMHA did not enable imprinting in day-4 chicks. Moreover, bilateral ablation of IMHA after imprinting training impaired recall. These results suggest that the IMHA is critical for memory acquisition downstream following T3 action in the IMM and further, that it receives and retains information stored in the IMM for recall. Furthermore, both an avian adeno-associated viral construct containing an anterograde tracer (wheat-germ agglutinin) and a retrograde tracer (cholera toxin subunit B) revealed neural connections from the IMM to the IMHA. Taken together, our findings suggest that hierarchical processes from the primary area (IMM) to the secondary area (IMHA) are required for imprinting.

Specific activity of cyclin-dependent kinase I is a new potential predictor of tumour recurrence in stage II colon cancer.

BACKGROUND: There are no established biomarkers to identify tumour recurrence in stage II colon cancer. As shown previously, the enzymatic activity of the cyclin-dependent kinases 1 and 2 (CDK1 and CDK2) predicts outcome in breast cancer. Therefore, we investigated whether CDK activity identifies tumour recurrence in colon cancer. METHODS: In all, 254 patients with completely resected (R0) UICC stage II colon cancer were analysed retrospectively from two independent cohorts from Munich (Germany) and Leiden (Netherlands). None of the patients received adjuvant treatment. Development of distant metastasis was observed in 27 patients (median follow-up: 86 months). Protein expression and activity of CDKs were measured on fresh-frozen tumour samples. RESULTS: Specific activity (SA) of CDK1 (CDK1SA), but not CDK2, significantly predicted distant metastasis (concordance index=0.69, 95% confidence interval (CI): 0.55-0.79, P=0.036). Cutoff derivation by maximum log-rank statistics yielded a threshold of CDK1SA at 11 (SA units, P=0.029). Accordingly, 59% of patients were classified as high-risk (CDK1SA ≥11). Cox proportional hazard analysis revealed CDK1SA as independent prognostic variable (hazard ratio=6.2, 95% CI: 1.44-26.9, P=0.012). Moreover, CKD1SA was significantly elevated in microsatellite-stable tumours. CONCLUSION: Specific activity of CDK1 is a promising biomarker for metastasis risk in stage II colon cancer.

Recurrence risk score based on the specific activity of CDK1 and CDK2 predicts response to neoadjuvant paclitaxel followed by 5-fluorouracil, epirubicin and cyclophosphamide in breast cancers.

BACKGROUND: We established the cell cycle profiling (C2P) assay for specific activity (SA; activity/expression) of cyclin-dependent kinases (CDKs). C2P risk score (C2P-RS) based on CDK1 and CDK2 SAs was significantly associated with relapse in breast cancer (BC). This study was conducted to investigate the predictive value of C2P-RS for neoadjuvant chemotherapy (NAC). PATIENTS AND METHODS: Among 124 eligible patients, 122 were treated with weekly paclitaxel followed by 5-fluorouracil, epirubicin and cyclophosphamide (P-FEC) and 2 were treated with paclitaxel monotherapy. C2P-RS was determined via C2P using frozen biopsy samples before NAC. RESULTS: Negative estrogen receptor (ER), negative progesterone receptor (PR), positive human epidermal growth factor receptor 2 (HER2), high Ki-67 expression and intermediate + high C2P-RS were significantly associated with high pathological complete response (pCR) rates compared with positive ER (30% versus 9%), positive PR (25% versus 6%), negative HER2 (34% versus 11%), low Ki-67 expression (24% versus 7%) or low C2P-RS (24% versus 9%), respectively. The combination of C2P-RS and Ki-67 had a stronger impact on pCR than each parameter alone, and a multivariate analysis showed that the combination was an independent predictor of pCR (odds ratio 3.3, 95% confidence interval 1.1-9.5). CONCLUSIONS: C2P-RS was significantly associated with pCR after P-FEC and may be a useful predictor for chemotherapy in BCs.

Isolation of a thermotolerant bacterium producing medium-chain-length polyhydroxyalkanoate.

AIMS: The aim of this study was to isolate a thermotolerant micro-organism that produces polyhydroxyalkanoates (PHAs) composed of medium-chain-length (mcl) HA units from a biodiesel fuel (BDF) by-product as a carbon source. METHODS AND RESULTS: We successfully isolated a thermotolerant micro-organism, strain SG4502, capable to accumulate mcl-PHA from a BDF by-product as a carbon source at a cultivation temperature of 45°C. The strain could also produce mcl-PHA from acetate, octanoate and dodecanoate as sole carbon sources at cultivation temperatures up to 55°C. Taxonomic studies and 16S rRNA gene sequence analysis revealed that strain SG4502 was phylogenetically affiliated with species of the genus Pseudomonas. This study is the first report of PHA synthesis by a thermotolerant Pseudomonas. CONCLUSIONS: A novel thermotolerant bacterium capable to accumulate mcl-PHA from a BDF by-product was successfully isolated. SIGNIFICANCE AND IMPACT OF THE STUDY: A major issue regarding industrial production of microbial PHAs is their much higher production cost compared with conventional petrochemical-based plastic materials. Especially significant are the cost of a fermentative substrate and the running cost to maintain a temperature suitable for microbial growth. Thus, strain SG4502, isolated in this study, which assimilates BDF by-product and produces PHA at high temperature, would be very useful for practical application in industry.

Interleukin-10 gene polymorphism reflects the severity of chronic immune thrombocytopenia in Japanese patients.

INTRODUCTION: T-helper cell type 1 (Th1) polarization of the immune response has been documented in patients with chronic immune thrombocytopenia (ITP). Interleukin (IL)-10 is the most important factor regulating Th1 and T-helper type 2 cytokine synthesis. This study evaluated the impact of IL-10 polymorphisms on both susceptibility to, and severity of, chronic ITP. METHODS: We analyzed -1082(G/A), -812(C/T), and -592(C/A) IL-10 polymorphisms in 90 patients with adult chronic ITP and 202 race- and sex-matched healthy controls. RESULTS: No significant differences in the genotype or haplotype frequencies were observed between the patient with chronic ITP and the control group. However, more patients with the -592AA genotype showed a severe thrombocytopenic state (platelet count <10 x 109/l) than those with the -592CC/CA genotypes (44.1%vs. 19.6%, P = 0.01). Furthermore, more patients with the ATA/ATA haplotype showed a severe thrombocytopenic state than those without the ATA/ATA haplotype (44.1%vs. 19.6%, P = 0.01). CONCLUSION: According to our data, patients with low producer type of IL-10 polymorphisms have more severe thrombocytopenia, suggesting that IL-10 gene polymorphisms may reflect the severity of ITP.

Air-leak syndrome following allo-SCT in adult patients: report from the Kanto Study Group for Cell Therapy in Japan.

We retrospectively investigated air-leak syndrome (ALS), including pneumothorax and mediastinal/s.c. emphysema, following allogeneic hematopoietic SCT. Eighteen patients (1.2%) developed ALS among 1515 undergoing SCT between 1994 and 2005 at the nine hospitals participating in the Kanto Study Group on Cell Therapy. The median onset of ALS was at 575 days (range: 105-1766) after SCT and 14 patients (77.8%) had experienced late onset noninfectious pulmonary complications (LONIPC) before ALS. Chronic GVHD (cGVHD) was the strongest risk factor for ALS (odds ratio 13.5, P=0.013 by multivariate analysis). Repeat SCT, male sex and age <38 years at the time of transplantation were also significant risk factors for ALS. Patients with ALS had a significantly worse survival rate than those without ALS (61.5 vs 14.9% at 3 years; P=0.000). The main cause of death was respiratory complications in 8 of the 18 patients. In conclusion, ALS is a rare complication of SCT that is more likely to occur in relatively young male patients with cGVHD and/or LONIPC. It is possible that better understanding and treatment of LONIPC may lead to prevention of ALS.

Hemodynamic studies of intracranial dural arteriovenous fistulas using arterial spin-labeling MR imaging.

Arterial spin-labeling (ASL) magnetic resonance imaging (MRI) enables non-invasive acquisition of the brain perfusion information in cerebrovascular disease. We investigated hemodynamic changes in intracranial dural arteriovenous fistulas (DAVFs) using ASL-MRI. ASL-MRI by a Q2TIPS sequence on a 3.0-Tesla MRI was performed for three patients with Cognard's IIa+b type of DAVFs before and after treatment. Perfusion images obtained by ASL-MRI (ASL images) before treatment were visually compared with those by single-photon emission computed tomography images (SPECT images). Increasing rates of temporal changes of regional perfusion values in ASL images (ASL values) before and after treatment were also calculated. In all three patients, ASL images before treatment demonstrated high perfusion in regions around the shunting areas, where normal or low perfusion were detected on SPECT images; thus, ASL images might have demonstrated the abundant arterial shunting flow via the fistulas. On days eight to 20 after treatment, ASL values around the shunt areas remained the same or decreased, and those in the regions other than the shunt areas increased in all three patients. This might have been due to a combination of the following: a decrease in shunt flow volume, an amelioration of venous congestion, and a sustained an upward shift in the autoregulation of the brain perfusion pressure. All regional ASL values decreased on days 112 and 120 after treatment in two patients, which possibly reflects a reduction in the upward shift in autoregulation. ASL-MRI might be useful for identifying the hemodynamic behavior of DAVFs before and after treatment.

Decrease in leptomeningeal ivy sign on fluid-attenuated inversion recovery images after cerebral revascularization in patients with Moyamoya disease.

BACKGROUND AND PURPOSE: The "ivy" sign that is identified on FLAIR images in patients with Moyamoya disease is considered to be leptomeningeal collaterals. The aim of our study was to evaluate the correlation between postoperative decrease in ivy sign and cerebral hemodynamic status in the bypass-established hemisphere. MATERIALS AND METHODS: Twenty-two patients with Moyamoya disease were enrolled. Postoperative changes in the ivy sign on FLAIR images were examined in each patient after bypass surgery. The correlation between postoperative changes in the ivy sign and hemodynamic status was examined in 10 patients by using SPECT. RESULTS: Of the 22 preoperative ivy-positive patients, 21 showed decreased ivy signs on the operative side. Average intervals between the operation day and the date when the decreased or vanished ivy sign was first recognized were 157.6 days in patients who underwent direct bypass and 212.2 days in patients who underwent indirect bypass. A postoperative decrease in ivy signs was found to be significantly correlated with an improved hemodynamic status of the surgically treated hemisphere, resulting in a postoperative increase in regional vascular reserve and a decreased proportion of the misery perfusion area (P < .01). CONCLUSIONS: Postoperative changes in the ivy sign can be used as a marker for identifying improved hemodynamics and also for testing the effectiveness of cerebral revascularization.

Clinical evaluation of the QuantiFERON-TB Gold test in patients with non-tuberculous mycobacterial disease.

OBJECTIVE: To evaluate the clinical usefulness of the QuantiFERON TB-2G (QFT-2G) test in patients with non-tuberculous mycobacterial (NTM) disease without a previous history of tuberculosis (TB). METHODS: The study consisted of 214 patients with NTM disease who satisfied the diagnostic guidelines of the American Thoracic Society. RESULTS: The causative microorganism was Mycobacterium avium in 83 patients, M. intracellulare in 80, M. kansasii in 33, M. marinum in 12, M. szulgai in 3, M. abscessus in 2 and M. chelonei in 1. The positive response rate of QFT-2G test result was 2% in 163 patients with M. avium-intracellulare complex (MAIC) disease, 52% in 33 with M. kansasii disease, 58% in 12 with M. marinum disease, 33% in 3 with M. szulgai disease, 0% in two with M. abscessus disease and 0% in one with M. chelonei disease. The positivity of the QFT-2G test was 52% in patients with NTM disease, thought to be because NTM possesses common M. tuberculosis-specific antigens. CONCLUSIONS: Although QFT-2G may be a useful diagnostic method to differentiate TB from MAIC disease, there are several problems to be resolved before it can be used as a diagnostic method for NTM disease (M. kansasii disease), including the determination of the positive cut-off level for QFT-2G test.

Discovery of a potent, metabolically stabilized resorcylic lactone as an anti-inflammatory lead.

With bioactivity-guided phenotype screenings, a potent anti-inflammatory compound f152A1 has been isolated, characterized and identified as the known natural product LL-Z1640-2. Metabolic instability precluded its use for the study on animal disease models. Via total synthesis, a potent, metabolically stabilized analog ER-803064 has been created; addition of the (S)-Me group at C4 onto f152A1 has resulted in a dramatic improvement on its metabolic stability, while preserving the anti-inflammatory activities.

Unilateral hemispheric proliferation of ivy sign on fluid-attenuated inversion recovery images in moyamoya disease correlates highly with ipsilateral hemispheric decrease of cerebrovascular reserve.

BACKGROUND AND PURPOSE: An ivy sign is considered to represent diffuse leptomeningeal collaterals found on fluid-attenuated inversion recovery (FLAIR) images of patients with Moyamoya disease. We evaluated the correlation between unilateral ivy proliferation in a hemisphere and cerebrovascular hemodynamic status to learn the clinical significance of the ivy sign. MATERIALS AND METHODS: A total of 35 patients with Moyamoya disease were included. Correlation between ivy dominance on FLAIR images and hemodynamic status with use of iodine 123 N-isopropyl-p-iodoamphetamine ((123)I-IMP) single-photon emission CT (SPECT) was evaluated. RESULTS: Distributional differences of ivy signs between both hemispheres were observed in 22 (64.7%) of 34 patients with a positive ivy sign, all of whom showed decreased vascular reserve/reactivity in the ivy-dominant hemisphere (IDH). The proportion of the stage II (misery perfusion) area to IDH was higher than that in the ivy less-dominant hemisphere (ILDH) in the quantitative analysis. The mean vascular reserve was lower in IDH than ILDH. There were 15 of 22 patients who had bypass surgery on IDH because of transient ischemic attack from ischemia of IDH. Patients with symmetric ivy distributions showed a variety of hemodynamic status. MR angiography (MRA) stage of IDH (2.95 +/- 0.39) was higher compared with ILDH (2.60 +/- 0.50; P < .05). Regional arteriocapillary circulation time ratio in IDH was longer compared with ILDH (P < .05). Ivy proliferation decreased in 10 (55.6%) of 18 patients who underwent bypass surgery during the follow-up period. CONCLUSIONS: Unilateral hemispheric ivy proliferation correlated highly with the existence of an ipsilateral decreased vascular reserve associated with the development of leptomeningeal collaterals in patients with Moyamoya disease.

Validation study of the prognostic value of cyclin-dependent kinase (CDK)-based risk in Caucasian breast cancer patients.

In a Japanese study, cyclin-dependent kinase (CDK) based risk determined by CDK 1 and 2 activities was associated with risk of distance recurrence in early breast cancer patients. The aim of our study was to validate this risk categorization in European early breast cancer patients. We retrospectively analyzed frozen breast cancer specimens of 352 Dutch patients with histologically confirmed primary invasive early breast cancer. CDK-based risk was determined in tumour tissues by calculating a risk score (RS) according to kinases activity and protein mass concentration assay without the knowledge of outcome. Determination of CDK-based risk was feasible in 184 out of 352 (52%) tumours. Median follow-up of these patients was 15 years. In patients not receiving systemic treatment, the proportions of risk categories were 44% low, 16% intermediate, and 40% high CDK-based risk. These groups remained significant after univariate and multivariate Cox-regression analysis. Factors associated with a shorter distant recurrence-free period were positive lymph nodes, mastectomy with radiotherapy, and high CDK-based risk. There was no significant correlation with overall survival (OS). CDK-based risk is a prognostic marker of distance recurrence of patients with early breast cancer. More validation would be warranted to use of CDK-based risk into clinical practice.

Determination of the specific activity of CDK1 and CDK2 as a novel prognostic indicator for early breast cancer.

BACKGROUND: We recently established a novel assay for specific activity (SA) of cyclin-dependent kinases (CDKs) using small tumor samples (>/=8 mm(3)). The aim of this study was to investigate the prognostic significance of CDK1SA and CDK2SA in human breast cancer. METHODS: CDK1SA and CDK2SA were determined in 284 breast cancer patients and their prognostic significance was investigated. RESULTS: Tumors with high CDK1SA and high CDK2SA showed significantly poorer 5-year relapse-free survival than those with low CDK1SA and low CDK2SA, respectively (66.9% vs 84.2% for CDK1SA; 43.6% vs 83.6% for CDK2SA). Moreover, combined analysis of CDK1SA and CDK2SA enabled the classification of breast tumors into high-risk and low-risk groups, where tumors in the high-risk group were strongly associated with unfavorable prognosis (5-year relapse-free survival 69.4% for the high-risk group and 91.5% for the low-risk group). Multivariate analysis showed that the risk determined by combined analysis of CDK1SA and CDK2SA is a significant (hazard ratio 3.09, P < 0.001) prognostic indicator for relapse, especially in node-negative patients (hazard ratio 6.73, P < 0.001). CONCLUSION: Determination of CDK1SA and CDK2SA may be useful in the prediction of outcomes in breast cancer patients and has potential for use as a routine laboratory test.

Risk of facial splashes in four major surgical specialties in a multicentre study.

This study analyses the results of face-shield blood spatter contamination at six medical facilities to determine exposure risk when facial protection is not used. Blood spatter exposure was evaluated on the basis of overall incidence, location of spatter on face shields, surgical specialty, risk for operating room staff, length of surgery and volume of blood loss. Six hundred face shields were evaluated for blood spatter contamination by visual inspection as well as by staining with leucomalachite green. The face shield was divided into three regions: Orbital (O-region), Paraorbital (P-region) and Mask (M-region). Visual examination detected blood spatter contamination in 50.5% (303/600) of the face shields, whereas leucomalachite green staining detected blood contamination in 66.0% (396/600). Blood contamination was 36.6% (220/600) in the O-region, 37.8% (227/600) in the P-region and 57.0% (342/600) in the M-region. Among operating room staff, the incidence of blood spatter was greatest among lead surgeons at 83.5% (167/200), followed by the first assistant at 68.5% (137/200) and the scrub nurse at 46.0% (92/200). By specialty, cardiovascular surgery was at highest risk with an incidence of 75.3% (113/150) followed by neurosurgery at 69.3% (104/150), gastrointestinal at 60.0% (90/150) and orthopaedic surgery at 60.0% (90/150).

Expression of CD55 and CD59 on peripheral blood cells in patients with lymphoproliferative disease of granular lymphocytes.

Lymphoproliferative disease of granular lymphocytes (LDGL) is a disorder characterized by the clonal expansion of granular lymphocytes. It has recently been shown that the clonal expansion of granular lymphocytes occurs in patients with paroxysmal nocturnal hemoglobinuria (PNH) in a subclinical fashion. To test the possibility that LDGL patients share a PNH phenotype, we obtained peripheral blood cells from 20 patients with LDGL and examined the expression of the glycosylphosphatidyl inositol (GPI)-anchored proteins, CD55 and CD59. Compared with normal controls, however, a defective expression of CD55/59 was not observed on either granulocytes or erythrocytes from LDGL patients. An unexpected finding was the significantly lower CD55/59 expression on granular lymphocytes from patients with CD16(+)CD56(-) phenotype LDGL than from patients with CD16(+)CD56(+) phenotype LDGL, or natural killer (NK) and NK/T lymphocytes from healthy individuals. The positive correlation between the expression of CD56 and CD55/59 might have some relevance to the functional properties of the CD56(+) subset of large granular lymphocytes.

Antimicrobial susceptibility and serotype distribution of Streptococcus pneumoniae isolated from patients with community-acquired pneumonia and molecular analysis of multidrug-resistant serotype 19F and 23F strains in Japan.

A nationwide study was undertaken to determine the susceptibility to penicillin and serotypes of Streptococcus pneumoniae in Japan. S. pneumoniae was isolated from 114 adult patients with community-acquired pneumonia over 22 months at 20 hospitals and medical centres in different regions in Japan. All but five isolates were from sputum. Forty-eight isolates (42.1%) were susceptible, 40 (35.1%) showed intermediate resistance (MIC, 0.12-1.0 microg/ml) and 26 (22.8%) were resistant (MIC, >or=2.0 microg/ml) to penicillin G. All isolates were susceptible to ceftriaxone (breakpoint 1 microg/ml), imipenem (4 microg/ml) and vancomycin (4 microg/ml). Most were resistant to erythromycin, clarithromycin and azithromycin; only two were resistant to levofloxacin. Differences were found in the distribution of serotypes among isolates showing susceptibility to penicillin (predominant types 3, 6B, and 19F), intermediate resistance (6B, 14, 19F, and 23F) and full resistance (19F and 23F). PFGE typing showed that 14 of the 25 strains of serotype 19F had a single DNA profile, pattern A, a pattern closely similar to that of the Taiwan multidrug-resistant 19F clone. Twelve pattern A strains were not susceptible to penicillin but carried the macrolide resistance gene mef(A). The DNA profiles of the 15 strains of 23F were also heterogeneous but six were highly similar (pattern b) yet distinct from the Spanish multidrug-resistant 23F clone although possibly related to the Taiwan multidrug-resistant 23F clone. The pattern b strains were not susceptible to penicillin and also harboured either mef(A) or erm(B). Our results indicate that multidrug-resistant pneumococci are spreading rapidly in Japan. Efforts to prevent the spread of the pandemic multidrug-resistant serotypes should be intensified.

Cerebral hemodynamics in Moyamoya disease: correlation between perfusion-weighted MR imaging and cerebral angiography.

BACKGROUND AND PURPOSE: In Moyamoya disease, the relationship between cerebral hemodynamics and angiographic findings has not been fully evaluated. The purpose of this study is to evaluate hemodynamics in Moyamoya disease with perfusion-weighted MR imaging (PWI) and cerebral angiography. METHODS: Twenty patients with Moyamoya disease were the subjects. Mean transit time (MTT) derived from PWI was calculated in the medial frontal lobes, the posterior frontal lobes, the occipital lobes, and the basal ganglia. From the angiographies, we classified the degrees of internal carotid artery (ICA) and posterior cerebral artery (PCA) stenoses as well as the degrees of Moyamoya vessels and leptomeningeal anastomosis (LMA). MTT in each region was compared with the angiographic findings. RESULTS: MTT positively correlated with the degree of ICA stenosis in the medial frontal (P < .01), posterior frontal (P < .001), and occipital (P < .001) lobes, as well as in the basal ganglia (P < .001). MTT correlated with the degree of PCA stenosis in the medial frontal (P < .001), posterior frontal (P < .001), and occipital (P < .001) lobes, as well as in the basal ganglia (P < .001). MTT correlated with the degree of Moyamoya vessels in the medial frontal (P < .05) and posterior frontal (P < .01) lobes. A multivariate analysis revealed that ICA and PCA stenoses and Moyamoya vessels were independent factors that prolonged MTT. CONCLUSION: Both ICA and PCA stenoses may influence overall cerebral perfusion in Moyamoya disease. The development of Moyamoya vessels may indicate hemodynamic impairment.

Role of NF-kappa B in regulation of apoptosis of erythroid progenitor cells.

Erythropoietin (EPO) and interferon-gamma (IFN-gamma) added to human erythroid progenitor cells purified from peripheral blood (erythroid colony-forming cells; ECFC) significantly reduces apoptosis as assessed by flow cytometry (FCM) using annexin V. To clarify the role of NF-kappaB in the regulation of the apoptosis of erythroid progenitor cells, cyclosporin A (CsA), which blocks dissociation of the NF-kappaB complex, was added to serum-free cultures of ECFC. CsA induced the apoptosis of ECFCs in the presence of EPO or IFN-gamma, but at different magnitudes. In the presence of a relatively low concentration of CsA (10 microm), apoptosis was induced only in cultures with EPO. The direct involvement of NF-kappaB was then assessed by Western blotting and confocal microscopy. In the presence of EPO, NF-kappaB was abundant both in the cytoplasm and in the nucleus, and nuclear expression was diminished after adding CsA. In contrast, NF-kappaB was undetectable in the nucleus in the presence of IFN-gamma. The effect of CsA on mitochondrial function was investigated by determining the DeltaPsim and reactive oxygen species production. CsA disturbed the transmembrane potential in the presence of either EPO or IFN-gamma, although the viability of the cells was maintained in the presence of IFN-gamma plus CsA. These results indicate that IFN-gamma reduced the apoptosis of erythroid progenitor cells through a unique signaling pathway that is independent of NF-kappaB translocation, and which is not mediated by modulating mitochondrial function, whereas EPO reduced apoptosis through NF-kappaB translocation to the nucleus.