Outbreak of acute glomerulonephritis in children: Observed association with the T1 subtype of group A streptococcal infection in Northern Kyushu,Japan

Group A streptococcal infection is associated with the occurrence of acute glomerulonephritis (AGN) and rheumatic fever (RF). A surveillance study in the Saga area, in northern Kyushu, Japan, showed a small variation in the reported number of group A streptococcal infections in the period 1988–94. However, of the AGN cases reported in this period, more than half were observed in 1992. In order to examine whether some change had occurred in the serotype distribution of Streptococcus pyogenes during the period, patients in the Saga area diagnosed as having group A streptococcal infection and patients with AGN or RF were analyzed. Serological T-typing of S. pyogenes was carried out for patients with group A streptococcal infections, and the association between the occurrence of AGN or RF and the distribution of each different T subtype was analyzed. M-typing of S. pyogenes was also carried out and the correlation between T and M types was examined. From 1988 to 1994, the annual number of patients with group A streptococcal infections in the Saga area showed a small variation, range 65–100 patients/year. Of the 42 patients with AGN and three with RF observed in this period, 27 with AGN (64%) and one with RF (33.3%) were detected in 1992. Only the T1 subtype increased in 1992; the other T subtypes showed little variation in incidence. The number of patients with the T1 subtype was significantly correlated with the occurrence of AGN by regression analysis (P < 0.01). Of the 170 subjects tested for both T and M subtypes, 44 of the 45 T1-typed subjects had the M1 protein. Our epidemiological study suggested that the T1 subtype of streptococcal infection was associated with an outbreak of AGN in 1992 in the Saga area.     

Recent Perspective on Coronary Bifurcation Intervention: Statement of the “Bifurcation Club in KOKURA”

The treatment of coronary bifurcation lesion remains a challenging issue even in the drug‐eluting stent era. Frequent restenosis and stent thrombosis have been recently shown to be related not only to geometrical gap or stent structural deformation but also to rheological disturbance. Low wall shear stress at the lateral side of the bifurcation is likely to cause atherosclerotic changes due to easy access of the macrophages that induce chemical mediators. The turbulent flow over stent metal may facilitate accumulation of platelets, which results in thrombosis. The jailed strut and excess metal overlap may increase these risks. Since dramatic changes of the coronary flow pattern at the bifurcation are closely related to the genesis of atherosclerosis, future bifurcation intervention technique should be considered to restore the original physiological state as well as the anatomical structure. This article summarizes the global consensus of the members of the Asian Bifurcation Club and European Bifurcation Club at the KOKURA meeting. It also provides a perspective of basic sciences relating to bifurcation anatomy, physiology, and pathology, in the search for a best strategy for bifurcation intervention. (J Interven Cardiol 2010;23:295–304)     

Cell proliferation, apoptosis, angiogenesis and growth rate of incidentally found renal cell carcinoma

BACKGROUND: Our previous study showed that the growth rate of incidentally found renal cell carcinoma (RCC) varied, and that the initial clinical and pathological features did not predict subsequent growth of the carcinoma. The objective of this study was to determine the relationships between cell proliferation, apoptosis, angiogenesis and the growth rates of these RCC. METHODS: We examined cell proliferation, apoptosis, and angiogenesis in 16 incidentally found cases of RCC. Cell proliferation was assessed by immunohistochemical staining with a Ki-67 antibody. Apoptosis was assessed by the terminal deoxynucleotidyl transferase (TdT) mediated deoxy-UTP biotin nick end labeling (TUNEL) technique. The Ki-67 labeling index (KI) and the apoptotic index (AI) were determined as the ratio of immunohistochemically positive cells per 1000 cancer cells. The KI/AI ratio was also determined. Angiogenesis was evaluated by CD34 immunostaining. Finally, we investigated the correlation between these parameters and the growth rate of primary lesions of incidentally found RCC. RESULTS: The KI ranged from 7 to 73 (median, 20), AI ranged from 6 to 171 (median, 26), and microvessel density (MVD) ranged from 21 to 673 (median, 265) for incidentally found RCC. Ki-67 labeling index, AI and MVD were not closely correlated to each other. Furthermore, these parameters were not associated with growth rates of incidentally found RCC. Only the KI/AI ratio was strongly correlated to the growth rate of incidentally found RCC (r = 0.709; P = 0.0083). CONCLUSION: Our results suggest that the balance between cell proliferation and apoptosis partly determines the growth rate of primary lesions of incidentally found RCC.     

Progress report on phase I/II clinical trial of Ad-OC-TK plus VAL therapy for metastatic or locally recurrent prostate cancer: Initial experience at Kobe University

There is no effective therapy for hormone-refractory prostate cancer and a novel therapeutic modality, such as a gene therapy, should be actively pursued. Previously, Gardner and Chung conducted a phase I clinical trial of Ad-OC-TK (recombinant adenoviral vector containing osteocalcin promoter-driven herpes simplex virus thymidine kinase gene) plus VAL (valacyclovir) for the treatment of hormone-refractory prostate cancer at the University of Virginia. We report on our ongoing phase I/II clinical trial of Ad-OC-TK plus VAL for the treatment of advanced prostate cancer at the Kobe University Hospital, Japan.     

Cold activation of complement in sera from patients with persistent hepatitis C virus infection on interferon therapy

The loss of haemolytic activity in sera during storage at low temperature (the cold activation of complement) was observed in 136 of 184 (74%) patients with chronic liver disease associated with hepatitis C virus (HCV) infection. This was more frequent than observed in the three of 40 (8%) patients with chronic hepatitis B (P < 0.001) or none in 43 normal controls (P < 0.001). Of 103 patients with chronic hepatitis C who had completed a full course of recombinant interferon-α2a therapy (total dose: 516×10⁶U), 40 responded completely and 21 responded partially, as judged by the normalization or decrease of alanine aminotransferase levels 6 months after the completion of therapy; 42 patients did not respond at all. The cold activation of complement persisted in five (13%) complete responders, less often than in 33 (79%) non-responders (P < 0.001). At the completion of interferon therapy, the cold activation of complement persisted in 12 of 54 patients despite the normalization of alanine aminotransferase. Spontaneous exacerbation of hepatitis occurred in seven of 12 (58%) patients with cold activation, which was more frequent than in the four of 42 patients (10%) without it (P < 0.01). The cold activation of complement disappeared along with the loss of HCV-RNA in five of six responders during the 6 month period after the completion of interferon therapy, while both cold activation and HCV-RNA persisted in all eight non-responders. These results indicate that the cold activation of complement may be useful as a marker of HCV viraemia for monitoring the response to interferon in patients with HCV infection.     

Left renal pelvis of male neonates is predisposed to dilatation

Dilatation of the renal pelvis has been observed as an ultrasonographic finding of ureteral reflux as well as hydronephrosis. However, little information is available on the prevalence of renal pelvis dilatation in neonates. We measured the inner pelvis dimension of the kidneys in 511 apparently healthy neonates (279 boys and 232 girls) using an ultrasound scanner to determine the prevalence of renal pelvis dilatation. Ninety per cent of the neonates had an inner dimension of both renal pelvises below 5 mm. The prevalence of left renal pelvis dilatation of 5 mm or more was significantly higher in the boys than in the girls, 25 (9%) compared to 5 (2%). In contrast, no significant difference was found in the prevalence of right renal pelvis dilatation between the sexes. In the boys, the prevalence of renal pelvis dilatation of 6 mm or more was significantly higher on the left side than on the right. Moreover, the left renal pelvis dilatation of the male neonates had a tendency to persist at 1 month of age. These findings suggest that the left renal pelvis of the baby boy may be predisposed to dilatation.     

Granulocyte-colony stimulating factor producing urothelial carcinoma of renal pelvis

We report a case of granulocyte-colony stimulating factor (G-CSF) producing urothelial carcinoma of the renal pelvis in a 39-year old man. The patient was admitted to Kobe University Hospital, Kobe, Japan, complaining of macrohematuria and a 6-month history of left abdominal swelling. Abdominal computed tomography showed a large mass in the left kidney and para-aortic lymph node enlargement. A remarkable degree of leukocytosis was detected without any acute infectious disease. Enzyme immunoassay of the serum demonstrated a remarkable high concentration of G-CSF. The patient underwent left nephroureterectomy and para-aortic lymphadenectomy. Histochemical examination revealed urothelial carcinoma. Immunohistochemical staining with an anti-G-CSF antibody demonstrated G-CSF secreting cells. The patient died 8 weeks after the surgical operation. To our knowledge, this is the second case of G-CSF producing urothelial carcinoma of renal pelvis reported in the English literature.     

Major basic protein binding to thrombomodulin potentially contributes to the thrombosis in patients with eosinophilia

Summary. The contribution of an eosinophil granule protein, major basic protein (MBP), to the pathogenesis of thrombosis seen in patients with eosinophilia was investigated. The sera from eosinophilic patients containing elevated levels of MBP inhibited thrombomodulin (TM) function as a cofactor for the thrombin-catalysed activation of protein C more significantly than those from normal individuals (means 48.5% v 17.4%, respectively). It was suggested that the binding of mature MBP in the sera to TM was electrostatic, because mature MBP (pi 10.9) bound to TM, whereas pro-MBP (pi 6.2) did not. The inhibition of TM cofactor activity by eosinophil granule proteins was mainly attributed to the mature MBP, because MBP-depleted eosinophil granule proteins did not inhibit TM cofactor activity significantly. This inhibition seemed to be due to the specific thrombin-binding to TM being blocked. We concluded that eosinophil granule proteins, particularly MBP, potentially contribute to the hypercoagulation seen in some conditions of eosinophilia, at least because of the inhibition of TM function as a cofactor of the anticoagulation system.     

BCG Immunotherapy as an Adjuvant to Surgery in Lung Cancer: A Randomized Prospective Clinical Trial

A protocol was drawn up and a prospective randomized study wascarried out to test the effectiveness of BCG on lung cancer.BCG obtained from the Japan BCG Institute was used. A dose of5.4 mg or 2–4 x 10⁸ viable organisms was administeredinto the arm by the tine technique. Administration of BCG wascarried out once before surgery and four times after surgery.Surgery consisted basically of radical lobectomy or pneumonectomywith complete mediastinal lymphadenectomy. The survival rate in the BCG administered group was significantly(P < 0.05) more than in the control group. Further, whenonly the cases that were treated strictly in accordance withthe protocol were taken into consideration, the effectivenessof BCG was even more significant (P < 0.02). The period ofobservation of these cases was from a minimum of 10 months toa maximum of 28 months. On the basis of these results, it can be said that BCG is beneficialin the treatment of lung cancer.     

DEVELOPMENT OF PROSTATE-SPECIFIC ANTIGEN PROMOTER-BASED GENE THERAPY FOR ANDROGEN-INDEPENDENT HUMAN PROSTATE CANCER

Purpose

The goal of this study is to develop a tissue-specific toxic gene therapy utilizing the prostate specific antigen (PSA) promoter for both androgen-dependent (AD) and androgen-independent (AI) PSA-secreting prostate cancer cells. Ideally this gene therapy would be effective without the necessity of exposing the target cells to circulating androgens.

Materials and Methods

An AI subline of LNCaP, an AD PSA-secreting human prostate cancer cell line, C4-2, was used in this study. Castrated mice bearing C4-2 tumors secrete PSA. A transient expression experiment was used to analyze the activity of two PSA promoters, a 5837 bp long PSA promoter and a 642 bp short PSA promoter, in C4-2 cells. A recombinant adenovirus (Ad-PSA-TK) carrying thymidine kinase under control of the long PSA promoter was generated. The tissue-specific activity of Ad-PSA-TK was tested in vitro and in vivo.

Results

The long PSA promoter had superior activity over short PSA promoter, and higher activity in C4-2 cells than in LNCaP cells. High activity of Ad-PSA-TK was observed in C4-2 cells in an androgen deprived condition. In vitro, Ad-PSA-TK was further demonstrated to induce marked C4-2 cell-kill by acyclovir in medium containing 5% FBS. No cell-kill was observed in control WH cells (a human bladder cancer cell line). In vivo, Ad-PSA-P-TK with acyclovir significantly inhibited subcutaneous C4-2 tumor growth and PSA production in castrated animals.

Conclusion

The 5837 bp long PSA promoter was active in the androgen free environment and could be used to target both androgen-dependent and independent PSA-producing prostate cancer cells in vitro, and prostate tumors in castrated hosts.