Distinct roles of neuropilin 1 signaling for radial and tangential extension of callosal axons

Cortical excitatory neurons migrate from their origin in the ventricular zone (VZ) toward the pial surface. During migration, these neurons exhibit a stellate shape in the intermediate zone (IZ), transform into bipolar cells, and then initiate radial migration, extending a trailing process, which may lead to an axon. Here we examined the role of neuropilin 1 (NRP1) in these developmental events. Both NRP1 mRNA and protein were highly expressed in the IZ, where stellate‐shaped cells were located. DiI labeling experiments showed that neuronal migration occurred normally in Nrp1 mutant mice up to embryonic day (E) 14.5, the latest day to which the mutant survives, with only subtle axonal defasciculation. However, interference with Nrp1 signaling at a later stage caused pathfinding errors: when a dominant negative form of Nrp1 was electroporated into the cortical VZ cells at E12.5 or E15.5 and examined perinatally, guidance errors were found in tangential axonal extension toward the midline. In contrast, no significant effect was noted on the migration of cortical excitatory neurons. These findings indicate that NRP1 plays an important role in the guidance of callosal axons originating from cortical excitatory neurons but does not support a role in their migration. Moreover, insofar as radial axonal extension within the cortical plate was unaffected, the present findings imply that molecular mechanisms for the axonal extension of excitatory neurons within the cortical plate are distinct from those in the white matter. J. Comp. Neurol. 514:215–225, 2009. © 2009 Wiley‐Liss, Inc.     

Pharmacokinetics/genotype associations for major cytochrome P450 enzymes in native and first- and third-generation Japanese populations: comparison with Korean, Chinese, and Caucasian populations

Application of foreign clinical data across geographic regions can accelerate drug development. Drug disposition can be variable, and identification of factors influencing responsible pharmacokinetic/pharmacogenomic approaches could facilitate the universal application of foreign data and reduce the total amount of phase III clinical trials evaluating risks in different populations. Our objective was to establish and compare genotype (major cytochrome P450 (CYP) enzymes)/phenotype associations for Japanese (native and first- and third-generation Japanese living abroad), Caucasian, Chinese, and Korean populations using a standard drug panel. The mean metabolic ratios (MRs) for the four ethnic groups were similar except for a lower activity of CYP2D6 in Caucasians and CYP2C19 in Asians. Genotype, not ethnicity, impacted the MR for CYP2C9, CYP2C19, and CYP2D6; neither affected CYP1A2, CYP2E1, and CYP3A4/5 activities. We conclude that equivalent plasma drug concentrations and metabolic profiles can be expected for native Japanese, first- and third-generation Japanese, Koreans, and Chinese for compounds handled through these six CYP enzymes.     

Mathematic modeling for prediction of waning immunity and timing of booster doses

Under an environment that a vaccination rate is low and an infectious disease is prevalent, it is thought that most vaccinee got additional immunity by natural infection. On the other hand, in the area where the incidence of disease has been reduced by high rate vaccination, it is also decreased the chance of additional immunity by natural infection. Therefore susceptible individuals are increased because of the waning immunity. In the community where a vaccination rate is high, it may be necessary to consider the booster vaccination for adolescent and adult even if one completed the primary vaccinations. It may also be important to explore the timing of booster dose. In this paper, we attempt to give a comprehensive explanation of mathematical model for predicting the antibody duration, and we introduce the role of mathematical model on a consideration to the need and timing of booster doses after the primary series.     

IFN-inducible protein 10 (CXCL10) regulates tubular cell proliferation in renal ischemia-reperfusion injury

Although renal tubular cell proliferation after acute tubular necrosis is an important and essential response in the recovery of renal dysfunction in acute renal failure, the precise factors and mechanisms of tubular cell regeneration remain unclear. Here, we describe our studies using a neutralizing antibody (Ab) against interferon-inducible protein of 10 kDa (IP-10; CXCL10) that indicate a role for CXCL10 in tubular cell proliferation after renal ischemia-reperfusion injury. Tissue necrosis and interstitial infiltrating numbers were comparable between anti-CXCL10 Ab-treated and control mice treated with IgG at the 24 and 48 h time points after reperfusion. In contrast, the numbers of Ki67-positive proliferating tubular cells were significantly increased in anti-CXCL10 Ab-treated mice 48 h after reperfusion. In accordance with the in vivo findings,in vitro studies using murine tubular epithelial cells indicated an antiproliferative effect of CXCL10 upon the intensity of cell proliferation and the number of Ki67-positive cells. These data suggest that CXCL10 plays a role in the regulation of tubular cell proliferation following renal ischemia-reperfusion injury.     

An open cohort study of bone metastasis incidence following surgery in breast cancer patients

Background  

To help design clinical trials of adjuvant bisphosphonate therapy for breast cancer, the temporal incidence of bone metastasis was investigated in a cohort of patients. We have tried to draw the criteria to use adjuvant bisphosphonate.     

Histological differences in new-onset IgA nephropathy between children and adults.

BACKGROUND: It is suggested that IgA nephropathy (IgAN) manifests differently in children vs adults on the basis of biopsy findings. However, this has been difficult to establish owing to the uncertainty of the timing of disease onset in adult IgAN. We addressed this question by comparing both histology and leucocyte accumulation in biopsies of recently diagnosed childhood and adult IgAN. METHODS: Biopsies taken within 2 years from the onset of renal abnormalities in 33 childhood (10 +/- 3 years of age) and 38 adult (35 +/- 6 years) cases of IgAN were examined for histological changes (cellularity in mesangial, endocapillary and extracapillary areas, matrix expansion, adhesions/crescents and interstitial damage), glomerular deposition of immunoglobulin and complement, and the presence of macrophages, activated macrophages and T cells by immunohistochemistry. RESULTS: Glomerular hypercellularity owing to increased cells in mesangial area was prominent in paediatric IgAN and significantly greater than in adult IgAN. In contrast, glomerular matrix expansion, crescent formation and interstitial damage were more severe in adults compared to paediatric IgAN. Indeed, glomerular hypercellularity correlated with proteinuria in paediatric but not in adult IgAN, whereas glomerular matrix correlated with proteinuria and renal function in adult but not in paediatric IgAN. The degree of C3c deposition was significantly greater in paediatric IgAN, while deposition of fibrinogen was greater in adult IgAN. Glomerular and interstitial CD68+ macrophages and a subset of sialoadhesin (Sn)+ activated macrophages were identified in both paediatric and adult IgAN, being significantly greater in number in adult IgAN. Glomerular leucocyte infiltration correlated with proteinuria while interstitial leucocyte infiltration correlated with interstitial damage in both groups. However, only the subset of Sn+ macrophages gave a significant correlation with renal function, glomerular hypercellularity and glomerular matrix. CONCLUSIONS: This study has demonstrated significant differences in the early glomerular lesions of IgAN in children vs adults. Furthermore, Sn+ activated macrophages are implicated in the pathogenesis of IgAN in both patient groups. The prognostic significance of these findings warrants further study.     

Pirfenidone prevents the progression of irreversible glomerular sclerotic lesions in rats

Summary: Pirfenidone (PFD) is a new drug which has been shown to prevent or even reverse the extracellular matrix accumulation in several organs. to examine the effect of PFD on the progressive glomerulosclerosis, we treated model rats with irreversible chronic renal disease per orally with 500 mg/kg bodyweight of PFD per day. the model rats were made by intravenous injection of anti-Thy-1 monoclonal antibody 1-22-3 at 1 h following unilateral nephrectomy, which results in chronic progressive glomerulosclerosis. Twenty-four hours later, 32 female Wistar rats were divided into two groups and were fed standard chow with (PFD group: P) or without PFD (control group: C). All rats were sacrificed on day 42. No significant difference in the bodyweight or the amount of chow intake was observed between the two groups. the remnant kidney was significantly ( P <0.05) heavier in C (2.11 ± 0.15 g) than in P (1.70 ± 0.13 g). This finding, together with light microscopic findings, showed that PFD administration resulted in the prevention of renal hypertrophy. On day 42, proteinuria in P (124.3 ± 31.9 mg/day) was significantly lower than in C (214.6 ± 8.1 mg/day), and P maintained significantly better renal function than C as judged by serum urea nitrogen and creatinine levels. Mean matrix score was less in P (178 ± 17) than in C (225 ± 22). Crescent formation was observed in 17% of glomeruli in P and in 35% in C. Tubulointerstitial lesions were also less severe in P. Furthermore, inflammation and sclerosis indices detected by immunohistochemistry (e.g. ED-1, OX8, TGF-beta α-smooth muscle actin, collagen type I, were less in P). These data suggest that PFD may be a promising agent for the prevention of progressive and irreversible glomerulosclerosis.     

OK432 inhibits experimental hepatic metastasis of colon adenocarcinoma ACL-15 in F344 rats

The effect of OK432 on hepatic metastasis, induced by inoculating 1 X 10⁶ ACL-15 cells from a rat colon adenocarcinoma cell line into the ileocolic vein of male F344 rats, was investigated in this study. Metastases were detected 14 days after inoculation in the control rats, however, pretreatment 3 days prior to the tumor cell inoculation with an anti-asialoGM1 antibody, which eliminates natural killer (NK) cell activity in vitro, increased the number of hepatic metastases, shortened the survival time, and decreased the NK activity of the nonparenchymal liver cells (NPC). In contrast, pretreatment with OK432 2 days prior to tumor inoculation significantly decreased the number of hepatic metastases, prolonged the survival time, and augmented the NK activity of the NPC, although treatment with OK432 3 or 7 days after inoculation did not decrease the number of hepatic metastases. Moreover, NPC from the OK432-pretreated rats had a marked antitumor effect against ACL-15 cells in the Winn's neutralization test. The results of this study indicate that pretreatment with OK432 before tumor cell inoculation inhibits hepatic metastasis in this experimental model, possibly by augmentating liver-associated NK activity.     

Esophageal squamous cell carcinoma: Pathology and prognosis

Between 1985 and 1992 a total of 403 patients with resected thoracic esophageal squamous cell carcinoma were evaluated histopathologically, and various pathologic findings related to survival were examined. Concerning depth of tumor invasion, 8 (2%) cases were pTis, 110 (27%) were pT1, 48 (12%) were pT2, 202 (50%) were pT3, and 35 (9%) were pT4. Lymphatic invasion was detected in 299 cases (74%), blood vessel invasion in 200 cases (49%), intramural metastasis in 45 (11%), and lymph node metastasis in 232 (58%). In pT1 carcinoma cases, 4% of mucosal carcinomas and 30% of submucosal carcinomas had lymph node metastasis. Tumors with deeper invasion had a higher incidence of lymph node metastasis: 74% of pT3 carcinomas and 83% of pT4 carcinomas. The sites of lymph node metastasis were divided into mediastinal, cervical, and abdominal fields; and rates of lymph node metastasis were 49%, 14%, and 41%, respectively. In all resected cases, the operative mortality rate was 3.2%, and the overall 5-year survival rate was 44.8%. The 5-year survival rate of patients with curative resection (R₀ and R₁) was 49.5%, whereas patients with palliative resection (R₂) did not survive more than 3 years. There was no significant difference in survival relative to tumor location. In curatively resected cases, the significant prognostic factors by multivariate analysis were pT category, vascular invasion, lymph node metastasis, and intramural metastasis. Prognosis of lymph node-positive cases did not depend on the positive node site. Patients with only one positive node had a better prognosis, and those with six or more positive nodes had a poor prognosis. Concerning lymph node metastasis, other factors that worsened prognosis were a positive node larger than 1 cm, two- to three-field metastasis, and positive cervical nodes in cases of lower-third esophageal carcinoma.

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Resumen Se analizaron desde el punto de vista histopatológico 403 pacientes, 348 hombres y 55 mujeres, sometidos a resección de carcinoma escamocelular del esófago torácico en el período 1985 a 1992, y se examinaron diversos hallazgos patológicos en relación a sobrevida. En cuanto a profundidad de invasión tumoral, 8(2%) casos fueron Tis, 110(38%) p T1, 48(12%) p T2, 202(50%) p T3 y 35(8%) p T4. Se detectó invasión linfática en 299 casos (74%), invasión de vasos sanguíneos en 200 (49%), metástasis intramurales en 45(11%) y metástasis ganglionares en 232 (58%). Entre los casos en estado p T1, 4% de los carcinomas mucosos y 30% de los submucosos tenían metástasis ganglionares.Los tumores con invasión más profunda exhibieron una mayor incidencia de metástasis ganglionares, 74% en los pacientes en estado pT3 y 83% en los estados pT4. La ubicación de las metástasis ganglionares fue dividida en tres campos: mediastinal, cervical y abdominal, y las ratas de metástasis ganglionares correspondientes fueron 49%, 14%, y 41%. La tasa de mortalidad operatoria fue 3.2% y la tasa global de sobrevida a 5 años fue 44.8%; para los casos con resección curativa (R0 y R1) ésta fue de 49.5%, en tanto que ninguno de los pacientes con resección paliative (R2) sobrevivió más allá de 3 años no se hallaron diferencias significativas en lo relativo a ubicación del cáncer.En los pacientes con resección curativa, los factores pronóstico de importancia significativa determinados por análisis multivariado fueron el estado pT, la invasión vascular, las metástasis ganglionares y las metástasis intramurales. El pronóstico en los pacientes con ganglios positivos no dependió de la ubicación de los ganglios afectados, y los pacientes con sólo un ganglio afectado tuvieron un mejor pronóstico, en tanto que aquellos con 6 o más ganglios afectados tuvieron un pronóstico pobre.En lo relativo a las metástasis ganglionares, otros factores que ensombrecieron el pronóstico fueron los ganglios mayores de 1 cm, metástasis a 2–3 campos y ganglios cervicales positivos cuando el carcinoma primario era del tercio inferior del esófago.

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Résumé Entre 1985 et 1992, 403 patients ayant eu une résection de leur cancer épidermoïde de l'oesophage thoracique ont eu une évaluation histopathologique corrélée avec la survie. En ce qui concerne la profondeur de l'invasion, huit cas (2%) étaient des pTis, 110 (38%) étaient des pT1, 48 (12%) étaient des pT2, 202 (50%) étaient des pT3, et 35 (8%) étaient des pT4. L'atteinte lymphatique a été détectée chez 299 (74%) patients, une invasion vasculaire dans 200 (49%) des cas, une résurgence intramurale dans 45 (11%) des cas et une atteìnte ganglionnaire chez 232 (58%) des cas. Dans le cas des tumeurs pT1, 4% des cancers de la muqueuse, et 30% des cancers de la sous-muqueuse étaient accompagnées de métastases ganglionnaires. Des tumeurs ayant une invasion plus profonde, les pT3 et les pT4 étaient associées à des métastases ganglionnaires dans 74% et 83% des cas. Les sites des métastases ganglionnaires étaient le médiastin, les chaînes cervicales, et l'abdomen chez, respectivement, 49%, 14% et 41% des cas. Parmi les cas de résection, la mortalité opératoire était de 3.2% et la survie globale à 5 ans étaient de 44.8%. La survie à 5 ans des patients ayant eu une résection à visée curative (R0 et R1) était de 49.5% alors qu'aucun des patients ayant eu une résection palliative (R2) n'étaient en vie à 3 ans. Il n'y avait aucune différence de survie selon la localisation tumorale. Chez les patients réséqués de façon curative, les facteurs pronostiques significatifs étaient la classe pT, l'invasion vasculaire, la métastase lymphatique, et l'invasion intramurale. Le pronostic des patients ayant une métastase ganglionnaire était indépendant de la localisation. Le pronostic des patients ayant un seul ganglion envahi était meilleur que le pronostic des patients ayant six ou plus de ganglions envahis. Le pronostic était moins bon lorsque la métastase ganglionnaire était plus grande que 1 cm, intéressait plus de 2–3 champs différents et lorsqu'elle intéressait la chaîne cervicale en cas de cancer du tiers inférieur de l'oesophage.