Hematopoietic stem cell and marrow stromal cell for spinal cord injury in mice

We compared the effects of hematopoietic stem cell and marrow stromal cell transplantation for spinal cord injury in mice. From green fluorescent protein transgenic mouse bone marrow, lineage-negative, c-kit- and Sca-1-positive cells were sorted as hematopoietic stem cells and plastic-adherent cells were cultured as marrow stromal cells. One week after injury, hematopoietic stem cells or marrow stromal cells were injected into the lesioned site. Functional recovery was assessed and immunohistochemistry was performed. In the hematopoietic stem cell group, a portion of green fluorescent protein-positive cells expressed glial marker. In the marrow stem cell group, a number of green fluorescent protein and fibronectin-double positive cells were observed. No significant difference was observed in the recovery between both groups. Both hematopoietic stem cells and marrow stromal cells have the potential to restore the injured spinal cord and to promote functional recovery.     

Elucidation with the protease alpha-chymotrypsin of the inhibitory modulating action of endogenous neuropeptide Y over sympathetic neurotransmission in rat vas deferens

The physiological role of endogenous neuropeptide Y (NPY) in sympathetic neurotransmission was examined in rat and guinea pig vas deferens (VD), using alpha-chymotrypsin (alpha-CT). NPY-like immunoreactivity was detected in the longitudinal muscle layer of VD densely in rats but sparsely in guinea pigs, and it disappeared following surgical denervation. Under blockade of the prejunctional alpha(2)-adrenergic autoinhibition, alpha-CT potentiated the phasic contraction in rat, but not guinea pig, VD induced by trains of transmural nerve stimulation (TNS) in a frequency-dependent manner, which was reproducible during repeated applications and not affected by pretreatment with capsaicin. In contrast, alpha-CT did not potentiate the twitch response or contractions induced respectively by a single pulse TNS or by direct electrical stimulation to the smooth muscle. Exogenously applied NPY suppressed the twitch response, which was cancelled by alpha-CT, and excitatory junction potentials, although it affected neither spontaneous junction potentials nor the direct electrical stimulation-induced contraction. These observations provided further evidence to support that NPY is released endogenously by TNS at high frequency, acting prejunctionally to suppress sympathetic neurotransmission. Thus, the protease alpha-CT proved itself to be a useful tool to reveal a functional role of endogenously released peptides.     

Serine/threonine kinase AKT is frequently activated in human bile duct cancer and is associated with increased radioresistance

The prognosis for patients with bile duct cancer (BDC) remains poor. Although BDC cells are essentially radioresistant, recent reports have suggested that radiation therapy, in addition to its palliative role in the management of BDC, may improve patient survival. A better understanding of the mechanisms that lead to cellular radioresistance may assist in the development of more effective BDC therapies based on radiotherapy in combination with radiosensitizing agents. The serine/threonine kinase AKT/protein kinase B, a downstream effector of phosphatidylinositol 3'-kinase, is a well-characterized kinase that is known to play a critical role in antiapoptotic signaling pathways. In this investigation, we sought to clarify the role of AKT signaling in the radioresistance in BDC cells. First, to examine whether activated AKT is expressed in BDCs, tumor specimens were obtained from 19 consecutive BDC cases. Immunohistochemical staining using an anti-phosphorylated-AKT antibody showed that phosphorylated (activated) AKT was expressed in cancer cells but not in neighboring normal mucosa in 16 cases (84.2%). Next, to evaluate the role of AKT activation in the regulation of BDC cell radiosensitivity, clonogenic assays were performed using the phosphatidylinositol 3'-kinase inhibitor LY294002 with and without irradiation. LY294002 inhibited AKT activation in BDC cells and, on irradiation, decreased clonogenic survival in a radiation dose-dependent manner. Only a small decrease in cell viability was observed in cells exposed to LY294002. Expression of constitutively active AKT in BDC cells resulted in decreased radiosensitivity, whereas a dominant-negative AKT increased radiosensitivity. Furthermore, constitutively active AKT also inhibited radiation-induced apoptosis. Collectively, these results indicate that activated AKT in BDC cells is associated with radioresistance and suggest that pharmacological or genetic modulation of AKT activity may have important therapeutic implications in BDC patients treated with radiation.     

Phase I, dose escalation and pharmacokinetic study of cediranib (RECENTIN™), a highly potent and selective VEGFR signaling inhibitor, in Japanese patients with advanced solid tumors

Purpose  To evaluate safety and tolerability of cediranib, a highly potent and selective vascular endothelial growth factor signaling inhibitor, in Japanese patients with advanced solid tumors refractory to standard therapies. Methods  In part A (n = 16), patients received once-daily oral cediranib (10–45 mg) to identify the maximum tolerated dose (MTD). In part B (n = 24), patients with non-small-cell lung cancer or colorectal cancer received multiple daily doses at the MTD. Results  Cediranib 30 mg/day was considered the MTD since 50% of evaluable patients receiving 45 mg/day experienced dose-limiting toxicities in part A (proteinuria and diarrhea n = 1, proteinuria n = 1, thrombocytopenia n = 1). The most common adverse events were diarrhea (n = 34) and hypertension (n = 32). Pharmacokinetic analysis confirmed cediranib as suitable for once-daily oral dosing. Of 32 evaluable patients, two had partial RECIST responses and 24 had stable disease ≥8 weeks. Conclusions  Cediranib was generally well tolerated at ≤30 mg/day in these Japanese patients and showed encouraging antitumor activity.     

Distribution of estimated glomerular filtration rate (eGFR) values in patients receiving contrast-enhanced magnetic resonance imaging

Purpose

The aim of this study was to elucidate the distribution of estimated glomerular filtration rate (eGFR) values in patients who underwent gadolinium-based contrast agent (GBCA)-enhanced magnetic resonance imaging (MRI) at different types of hospitals.

Materials and methods

We retrospectively studied 2,550 patients who underwent MRI at five institutions. We recorded the date and value of each patient??s eGFR test. The distribution of eGFR values was compared with that in the general Japanese population.

Results

A total of 84.3% of patients had their eGFRs evaluated before GBCA-enhanced MRI. Of these, 84.7% were evaluated within 3?months before the GBCA-enhanced MRI, and 1.3% were evaluated on the day of the GBCA-enhanced MRI. A total of 87.2% of patients tested had an eGFR of ??60?ml/min/1.73?m²; 12.8% had an eGFR of <60 and ??30?ml/min/1.73?m², and no patients had an eGFR of <30?ml/min/1.73?m².

Conclusion

The rate of renal function evaluation differed among hospitals. The prevalence of low eGFR values was greater in Juntendo Tokyo Koto Geriatric Medical Center than in the other hospitals, and the prevalence of low eGFR values was greater in patients who underwent GBCA-enhanced MRI than in the general Japanese population.     

An improved method for estimating the heart-to-mediastinum ratio from cardiac sympathetic nerve imaging with low-energy high-resolution collimators

Background

Septal penetration causes underestimation of the heart-to-mediastinum (H/M) ratio in cardiac ¹²³I-metaiodobenzylguanidine (MIBG) imaging with a low-energy high-resolution (LEHR) collimator. We aimed to improve the method of estimating the H/M ratios using the LEHR collimator.

Methods and Results

4 hours after ¹²³I-MIBG injection, 40 patients were imaged successively with the medium-energy (ME) and LEHR collimators using gamma cameras having 3/8-inch crystals. Severe underestimation of the H/M ratios was observed with the LEHR collimator when compared to the ME collimator. Narrowing the energy window width did not reduce the underestimation. Application of ¹²³I-dual-window (IDW) correction using a narrow or wide subwindow reduced the underestimation substantially but not entirely. The H/M ratios estimated from the LEHR images with or without IDW correction were corrected based on their correlations with the ratios estimated from the ME images. This empiric correction removed systematic underestimation, and residual errors were reduced when the H/M ratios after IDW correction were converted using the empiric equation. The conversion equation was successfully applied to the correction of the H/M ratios determined in another 40 patients using a 5/8-inch crystal.

Conclusions

In estimating the H/M ratios using an LEHR collimator, empiric correction combined with IDW correction improves concordance with ME-based values in comparison with empiric correction alone.     

Energy metabolism and turnover are increased in mice lacking the cholecystokinin-B receptor

Cholecystokinin (CCK) is an important gastrointestinal hormone as well as a neurotransmitter. Two types of CCK receptors, types A and B, have been identified. The CCK-A receptor is involved in satiety, food intake and behavior, whereas the B receptor is involved in anxiety. We recently produced CCK-A, -B and AB receptor knockout mice to study the role of these receptors in energy metabolism. Daily energy intake and expenditure were significantly greater in CCK-BR(-/-) and CCK-AR(-/-)BR(-/-) mice than CCK-AR(-/-) and wild-type [CCK-AR(+/+)BR(+/+)] mice. Relative liver and kidney weights (g/kg body) were significantly greater in CCK-AR(-/-)BR(-/-) mice than in wild-type mice. Energy metabolism and energy turnover were increased in mice with a disruption of the CCK-BR gene, although the underlying mechanism is unknown.     

Pathological Aspects of Radiofrequency Catheter Ablation of the Canine Atrioventricular Node and Bundle of His

Radiofrequency catheter ablation of the atrioventricular (AV) node or bundle of His was performed in 12 adult mongrel dogs. The aim was to create chronic incomplete AV block (first- and second-degree AV block) and to examine the histopathology of the ablated lesions. However, the late electrophysiological results (2 4 weeks follow up) were various: normal in 2 dogs, mild PR prolongation (< 50%) in 2 dogs, first-degree AV block (PR prolongation a 50%) in 2 dogs, second degree AV block in 2 dogs, complete AV block in 4 dogs. The maximally ablated area (%) of the atrioventricular conduction system in serial histologic sections from dogs with these conditions was 69%, 75%, 89.5%, 95% and 99.5%, respectively. The number of intact conduction cells at the maximally ablated site varied from 6 to 30 in the four cases of incomplete AV block. The mean ablated volume (%) of either the AV node or penetrating His bundle correlated roughly with the degree of AV block. The ablated lesions were well demarcated and almost replaced by dense fibrous tissue at 4 weeks. Interruption (3 dogs) or thinning (1 dog) of the endocardial elastic lamellae was detected, in association with endocardial thickening (mean 913 μm). Endocardial thrombi were found in 3 dogs (2 fresh, 1 organized). We conclude that radiofrequency catheter ablation does not cause severe complicated lesions. Several possible conditions for creating chronic incomplete AV block are discussed. Acta Pathol Jpn 41: 487–498, 1991.