Treatment and prognosis of patients with paraplegia or quadriplegia because of metastatic spinal cord compression in prostate cancer.

Metastatic spinal cord compression (MSCC) is a serious complication of metastatic prostate cancer (PCa). This study retrospectively evaluated patients who presented with paraplegia or quadriplegia because of MSCC of PCa. Of 847 patients with PCa who were treated between 1989 and 1998, 26 (3.1%) demonstrated paraplegia or quadriplegia because of MSCC. Characteristics, treatment efficacy, and prognosis of these patients were analyzed. In total, 15 cases became paraplegic despite androgen ablation therapy (Group I). Average time to paraplegia from initial hormonal treatment was 34 months. Out of nine cases who underwent radiation therapy (RT) to spinal lesions with/without chemotherapy, one patient became ambulatory. However, this patient subsequently had recurrent compression. Two cases had remission of paralysis. Two cases underwent laminectomy plus RT and in one case paralysis improved. MSCC was the first indication of PCa in 11 cases (Group II). Two cases underwent laminectomy plus hormone therapy and nine cases underwent hormone therapy alone. Four patients became ambulatory and two cases showed improved motor capacity. Average interval from paraplegia to death was 7.4 months in Group I and 27.1 months in Group II. However, there was no statistical difference in these two groups on disease-specific survival from the start of initial treatment. It is difficult to recover the ability to walk if paraplegia or quadriplegia occurs in PCa patients although decompression surgery plus hormone therapy seemed to impair the prognosis. Stage M1 patients with paraplegia had survival rates as good as stage M1 patients without paralysis. This should encourage an aggressive treatment approach. However, for patients with hormone-independent disease there seems to be no effective treatment and prognosis is poor.

Pelvic exenteration for advanced colorectal cancer with reconstruction of urinary and sphincter functions.

BACKGROUND: Total pelvic exenteration (TPE) for the treatment of advanced colorectal cancer usually involves a double stoma for faecal and urinary excretion, which reduces patient quality of life. In this study, a stomaless reconstruction method for patients normally requiring TPE was evaluated. METHODS: Five patients underwent stomaless TPE. After removal of the tumour with an adequate surgical margin, the urethra was transected at the urogenital diaphragm and the rectum at the anal canal. An ileal neobladder was constructed and coloanal anastomosis was performed. The major omentum was used to construct a septum between the anastomoses. A transgastric ileus tube was used as an intestinal stent to prevent ileus. RESULTS: All patients were alive 12-39 months after operation. Faecal continence was preserved in four patients whose diverting colostomies were closed. All five patients were able to void urine spontaneously, with daytime continence. All but one, in whom cancer recurred, were mobile in the community. CONCLUSION: Stomaless TPE may be considered for locally advanced colorectal cancers that invade the genitourinary organs, provided that neither the anal canal nor the urogenital diaphragm is affected.

Prostate adenocarcinoma producing syndrome of inappropriate secretion of antidiuretic hormone.

The syndrome of inappropriate secretion of antidiuretic hormone (ADH) was recognized in a 68-year-old man with a poorly differentiated metastatic adenocarcinoma of the prostate. Elevated levels of ADH were found in the tissues of the primary tumor and lymph node metastasis. The patient's clinical course is detailed and the pathophysiology of this syndrome is discussed. To our knowledge, this case is the ninth reported case of syndrome of inappropriate secretion of ADH with adenocarcinoma of the prostate. Antidiuretic hormone activity was proven in only three cases including this case.

Role of bundle-forming pilus of enteropathogenic Escherichia coli in host cell adherence and in microcolony development.

Enteropathogenic Escherichia coli (EPEC) adheres to epithelial cells and forms microcolonies in localized areas. Bundle-forming pili (BFP) are necessary for autoaggregation and the formation of microcolonies. In this study, we show that BFP, expressed by EPEC on epithelial cells, disappeared with the expansion of the microcolony. Bacterial dispersal and the release of BFP from the EPEC aggregates were induced by contact with host cellular membrane extract. In addition, BFP-expressing EPEC adhered directly to cell surfaces, in preference to attaching to pre-formed microcolonies on the cells. These results suggested that BFP mediate the initial attachment of EPEC through direct interaction with the host cell rather than through the recruitment of unattached bacteria to microcolonies on the cell.

Inducible nitric oxide synthase expression and nuclear factor-kappaB activation in alveolar type II cells in lung injury.

Alveolar type II cells (type II cells) play a crucial role in the progression and repair of lung inflammation and injury. We investigated whether inducible nitric oxide synthase (iNOS) was expressed and nuclear factor-kappaB (NF-kappaB) was activated in type II cells in lung injury. After injecting lipopolysaccharide (LPS) or saline in the rat, the lungs were excised and type II cells were isolated. iNOS and its mRNA were expressed both in lung tissue and isolated type II cells in response to LPS. The lungs from saline-treated rats showed only minimal expression of iNOS. Electrophoretic mobility shift assay revealed that expression of NF-kappaB in the nuclear extracts was augmented by LPS, and p5O/NFkappaB was expressed in type II cells in LPS-treated rats. Intraperitoneal dexamethasone almost completely inhibited the iNOS expression and attenuated the activation of NF-kappaB in the LPS-treated lung. These findings suggest that type II cells can be a source of NO production in lung injury,and that the effects of corticosteroids may be in part through inhibition of both iNOS expression and NF-kappaB activation.

Transurethral holmium: YAG laser prostatectomy using a side-firing fiber for bladder outlet obstruction due to benign prostatic enlargement: urodynamic evaluation of surgical outcome.

OBJECTIVES: To prospectively assess the efficacy of transurethral holmium (Ho):YAG laser prostatectomy using a side-firing fiber in patients with bladder outlet obstruction due to benign prostatic enlargement (BPE) from the standpoint of urodynamics. METHODS: 32 male patients with BPE aged 53-83 (mean 69.4) years were operated on. All patients, excluding 3 with urinary retention, were evaluated with the International Prostatic Symptom Score (IPSS), Quality of Life (QOL) score and uroflowmetry up to 12 months postoperatively, and a pressure/flow study was performed before and 3 months after the operation. RESULTS: The total IPSS score, QOL score, average and maximum flow rates improved significantly (p<0.0001) at 12 months postoperatively. In the pressure/flow study, detrusor opening pressure, maximum detrusor pressure, detrusor pressure at maximum flow, minimum urethral opening pressure, and Abrams-Griffiths number decreased significantly (p<0.0001, p = 0.0001, p<0.0001, p = 0.0019 and p<0.0001, respectively) 3 months postoperatively. Detrusor instability disappeared in 12 of 17 patients and remained in 2. CONCLUSIONS: Transurethral Ho:YAG laser prostatectomy was found to be effective for the treatment of bladder outlet obstruction due to BPE.

Induction of CD4+ regulatory T cells by 12-O-tetradecanoylphorbol 13-acetate in mice. Part 1: The strain difference in this induction.

12-O-Tetradecanoylphorbol 13-acetate (TPA), an activator of signal transduction, induced antigen-nonspecific regulatory T (Tr) cells for delayed-type hypersensitivity (DTH) in the spleen. A marked strain difference in the induction of Tr cells was observed when the study was performed by using the several strains of mice at 6-8 weeks old. TPA painting induced CD4+Tr cells in C3H/He (H-2k), C3H/HeN (H-2k), DBA/2 (H-2d) and AKR/N (H-2k) mice, but not in C57BL/6 (H-2b), C57BL/10 (H-2b), BALB/c (H-2d) and A/J (H-2a). Regulatory cells were also induced by incubating spleen cells from unprimed mice with TPA in vitro and were seemed to act by the production of soluble factor(s). A downregulatory activity of the soluble factor(s) was abrogated by SXC-1 (anti-IL-10 monoclonal antibody), but not by SXC-2 (anti-IL-10 monoclonal antibody) and anti-IL-4. For purification of the factor(s), we established the T cell hybridoma 4C5-1 by the fusion of spleen cells from TPA-treated C3H/He mice with AKR thymoma Bw5147 cells. The 4C5-1 cells secrete the factor(s) which can inhibit DTH response. The inhibitory activity of the factor(s) could be neutralized by SXC-1, but not by SXC-2, anti-IL-4, anti-IL-6 and anti-TGF-beta antibodies. The factor(s) could not affect the proliferation and IFN-gamma production of alpha s1-casein-specific 3D20 Th1 cells. The factor(s) termed DIF (DTH Inhibitory Factor) may be a novel cytokine, since they have reduced the footpad swelling response by local injection, and have no immune crossreactivity with the DTH regulatory cytokines and no inhibitory activity for in vitro Th1 response.

Structural and functional characterization of IS679 and IS66-family elements.

A new insertion sequence (IS) element, IS679 (2,704 bp in length), has been identified in plasmid pB171 of enteropathogenic Escherichia coli B171. IS679 has imperfect 25-bp terminal inverted repeats (IRs) and three open reading frames (ORFs) (here called tnpA, tnpB, and tnpC). A plasmid carrying a composite transposon (Tn679) with the kanamycin resistance gene flanked by an intact IS679 sequence and an IS679 fragment with only IRR (IR on the right) was constructed to clarify the transposition activity of IS679. A transposition assay done with a mating system showed that Tn679 could transpose at a high frequency to the F plasmid derivative used as the target. On transposition, Tn679 duplicated an 8-bp sequence at the target site. Tn679 derivatives with a deletion in each ORF of IS679 did not transpose, finding indicative that all three IS679 ORFs are essential for transposition. The tnpA and tnpC products appear to have the amino acid sequence motif characteristic of most transposases. A homology search of the databases found that a total of 25 elements homologous to IS679 are present in Agrobacterium, Escherichia, Rhizobium, Pseudomonas, and Vibrio spp., providing evidence that the elements are widespread in gram-negative bacteria. We found that these elements belong to the IS66 family, as do other elements, including nine not previously reported. Almost all of the elements have IRs similar to those in IS679 and, like IS679, most appear to have duplicated an 8-bp sequence at the target site on transposition. These elements have three ORFs corresponding to those in IS679, but many have a mutation(s) in an ORF(s). In almost all of the elements, tnpB is located in the -1 frame relative to tnpA, such that the initiation codon of tnpB overlaps the TGA termination codon of tnpA. In contrast, tnpC, separated from tnpB by a space of ca. 20 bp, is located in any one of three frames relative to tnpB. No common structural features were found around the intergenic regions, indicating that the three ORFs are expressed by translational coupling but not by translational frameshifting.

Comparison of bacteriological, genetic and pathological characters between Escherichia coli O115a,c:K(B) and Citrobacter rodentium.

Murine pathogenic Escherichia coli O115a,c:K(B) (MPEC) is the causative agent of mouse megaenteron, the pathology of which resembles that of transmissible murine colonic hyperplasia caused by Citrobacter rodentium. We compared their genetic and pathological features to reveal the relationship between these two bacteria. To evaluate the genetic distances, 16S rDNA genes were sequenced and biochemical reactions were tested. Mouse strain susceptibility tests, using CF1 MPEC-susceptible germfree mice and BALB/cA(Jic) resistant mice were performed. MPEC strains and C. rodentium showed more than 99.6% identity by comparison of 16S rDNA gene sequences. All results from biochemical reactions and the mouse strain susceptibility tests were identical. It is proposed that MPEC should be reclassified as C. rodentium.

Effect of 4-(4-chlorobenzyl)pyridine on rat hepatic microsomal cytochrome P450 and drug-metabolizing enzymes in vivo and in vitro.

The effect of 4-(4-chlorobenzyl)pyridine (4-CBP) on rat hepatic microsomal cytochrome P450 (P450) and its molecular species (CYP2B1, 2E1, 3A2, 2C11, and 2C12), and on drug-metabolizing enzyme activities were examined in vivo and in vitro. Treatment of rats with 4-CBP resulted in the induction of P450 and drug-metabolizing enzymes in a dose-dependent manner, but it was markedly inhibitory at higher dose levels. Immunoblot analyses revealed that 4-CBP induces both CYP2B1 and 2E1; however, both were decreased by increasing the dose of 4-CBP. The in vitro inhibitory experiment revealed that 4-CBP strongly inhibited benzphetamine N-demethylase activity, but not dimethylnitrosamine N-demethylase activity. The present findings provide information on the induction and inhibition effect of chlorinated benzylpyridine on hepatic microsomal P450s and drug-metabolizing enzymes in vivo and in vitro.

Complete genome sequence of enterohemorrhagic Escherichia coli O157:H7 and genomic comparison with a laboratory strain K-12.

Escherichia coli O157:H7 is a major food-borne infectious pathogen that causes diarrhea, hemorrhagic colitis, and hemolytic uremic syndrome. Here we report the complete chromosome sequence of an O157:H7 strain isolated from the Sakai outbreak, and the results of genomic comparison with a benign laboratory strain, K-12 MG1655. The chromosome is 5.5 Mb in size, 859 Kb larger than that of K-12. We identified a 4.1-Mb sequence highly conserved between the two strains, which may represent the fundamental backbone of the E. coli chromosome. The remaining 1.4-Mb sequence comprises of O157:H7-specific sequences, most of which are horizontally transferred foreign DNAs. The predominant roles of bacteriophages in the emergence of O157:H7 is evident by the presence of 24 prophages and prophage-like elements that occupy more than half of the O157:H7-specific sequences. The O157:H7 chromosome encodes 1632 proteins and 20 tRNAs that are not present in K-12. Among these, at least 131 proteins are assumed to have virulence-related functions. Genome-wide codon usage analysis suggested that the O157:H7-specific tRNAs are involved in the efficient expression of the strain-specific genes. A complete set of the genes specific to O157:H7 presented here sheds new insight into the pathogenicity and the physiology of O157:H7, and will open a way to fully understand the molecular mechanisms underlying the O157:H7 infection.

The impact of a 4 cm. cutoff point for stratification of T1N0M0 renal cell carcinoma after radical nephrectomy.

PURPOSE: The 1997 TNM classification defines T1 tumors as those smaller than 7 cm. Recently, a cutoff point of 4 cm. has been proposed to create a subclass of T1 tumors. We evaluated the validity of this cutoff point by assessing the pathological findings and prognoses of patients with T1N0M0 renal cell carcinoma following radical nephrectomy. MATERIALS AND METHODS: We reviewed the hospital charts of 333 patients with T1N0M0 tumors, followed as long as 282 months (median 63) after radical nephrectomy. The validity of tumor size cutoff point for predicting survival outcome was tested in relation to other prognostic factors, including patient age, tumor position, nuclear grade, tumor histopathology and degree of microscopic venous invasion. RESULTS: During followup 32 patients (9.6%) had tumor recurrence and 21 (6.3%) died of renal cell carcinoma. A 5 cm. cutoff point maximized the differences in cancer specific survival rates and a 4 cm. cutoff point maximized the differences in disease-free survival rates. Tumor size was directly related to microscopic venous invasion and nuclear grade, which are significant prognostic factors, and a 4 cm. cutoff point enhanced these relationships. CONCLUSIONS: Tumor size is an important prognostic factor for patients with T1N0M0 renal cell carcinoma. A cutoff point of 4 cm. is practical for dividing the T1N0M0 classification into T1a and T1b subclasses.

Aberrant expression of Pax-2 mRNA in renal cell carcinoma tissue and parenchyma of the affected kidney.

BACKGROUND: Pax proteins are transcription factors that demonstrate oncogenic properties and appear to play a crucial role in ontogenesis. Pax-2 is expressed in early kidney organogenesis, Wilms' tumor and renal cell carcinoma. In order to determine whether the expression of Pax-2 mRNA is a frequent and specific event in renal cell carcinoma, its expression in nephrectomized specimens and cell lines was investigated. METHODS: The expression of Pax-2 mRNA was examined by reverse transcription polymerase chain reaction in 55 nephrectomized specimens, nine renal parenchyma specimens from patients without renal cell carcinoma and 16 cell lines from various malignant diseases. RESULTS: All tumor tissue specimens expressed Pax-2 mRNA. In addition, 38 of 55 specimens from the renal parenchyma of the affected kidney expressed Pax-2 mRNA. In contrast, only two of the nine kidney specimens from patients without renal cell carcinoma expressed Pax-2 mRNA, indicating that expression of this protein is significantly higher in renal cell carcinoma (P < 0.01). All three cell lines from renal cell carcinoma expressed Pax-2. In contrast, Pax-2 was only expressed in two of three cell lines from transitional cell carcinoma and in none of the other lines. CONCLUSION: The results indicate that Pax-2 expression is a frequent and highly specific event in renal cell carcinoma.

Characterization of mouse GBP28 and its induction by exposure to cold.

OBJECTIVE: To investigate whether the expression of the novel adipose tissue-specific protein GBP28 in adipose tissue and serum are altered in mice under a variety of conditions. DESIGN: Mice were fed a high-fat diet for 4 weeks, fasted for 48 h or exposed at 4 degrees C. SUBJECTS: C57BL/6J mouse, male, 4--6 weeks old. MEASUREMENTS: GBP28 mRNA, GBP28 protein, blood glucose, insulin and fad pad weight of the mice. RESULTS: We first confirmed that the mouse has GBP28 and its characteristics are the same as human GBP28. Serum concentration and mRNA levels of GBP28 significantly increased in the mice exposed to cold. CONCLUSION: GBP28 may play a role in homeostasis, regulating body temperature and basal metabolic rate in response to changing environmental conditions. International Journal of Obesity (2001) 25, 75-83

Serum immunosuppressive acidic protein as a potent prognostic factor for patients with metastatic renal cell carcinoma.

BACKGROUND: Estimation of survival probability of individual patients with metastatic renal cell carcinoma was difficult owing to diverse prognostic factors. We analyzed serum immunosuppressive acidic protein (IAP) levels and the cutoff value, then tested its validity for assessing patients' prognoses. METHODS: Serum IAP was measured longitudinally in 84 patients with metastatic disease. Before therapy, cutoff levels of IAP were tested every 20 microg/ml between 600 and 1200 microg/ml. The prognostic importance of IAP and its cutoff level was estimated. RESULTS: The cutoff level of IAP was set at 800 microg/ml for 40 patients who had metastatic disease with the primary tumor in situ and for 44 patients with recurrent disease. IAP was found to be a significant prognostic factor for both patient groups. CONCLUSIONS: Serum IAP is an important prognostic factor for patients with metastatic renal cell carcinoma. Stratification of patients according to prognosis is feasible using the cutoff level.

TIMP-1 promotes VEGF-induced neovascularization in the retina.

Proteolysis of vascular basement membranes and surrounding extracellular matrix is a critical early step in neovascularization. It requires alteration of the balance between matrix metalloproteinases (MMPs) and proteins that bind to and inactivate MMPs, tissue inhibitors of metalloproteinases (TIMPs). TIMP-1 has been demonstrated to inhibit neovascularization in chick chorioallantoic membranes. However, TIMP-1 has also been shown to either promote or inhibit cell proliferation and migration in different settings. To determine whether genetic alteration of the MMP/TIMP-1 ratio would alter retinal neovascularization, we crossed mice that express vascular endothelial growth factor (VEGF) in photoreceptors with TIMP-1-deficient mice or mice that overexpress TIMP-1. Compared to VEGF transgene-positive/TIMP-1-sufficient mice, VEGF transgene-positive/TIMP-1-deficient mice showed smaller neovascular lesions. There was also no difference between the two groups of mice in the appearance of the neovascularization by light or electron microscopy. Compound VEGF/TIMP-1 transgenic mice had increased expression of both VEGF and TIMP-1 in the retina, and had more neovascularization than mice that had increased expression of VEGF alone. These gain- and loss-of-function data suggest that alteration of the TIMP-1/MMP ratio modulates retinal neovascularization in a complex manner and not simply by altering the proteolytic activity and thereby invasiveness of endothelial cells.

Prognostic significance of changes in prostate-specific antigen in patients with metastasis prostate cancer after endocrine treatment.

Patients with metastatic prostate cancer respond to androgen withdrawal therapy, but progression to androgen independence is frequently observed. To clarify the predictor of response to endocrine therapy, the role of PSA changes and the prognosis of the patients were evaluated in 115 Japanese cases of prostate cancer with distant metastases treated with androgen withdrawal therapy. When patients were divided according to the pretreatment PSA value (high, > or = 500, median; 500 > PSA > or = 100, low; 100 >), patients whose initial PSA levels were high had a worse cause-specific survival. PSA value at 3 or 6 months following endocrine treatment, PSA nadir, and percent decrease of PSA were associated with prolonged survival. Clinical relapse was observed in 68 patients. Patients with distant recurrence had shorter time to PSA elevation than those with local recurrence. In metastatic prostate cancer patients treated with androgen withdrawal, serial measurement of PSA could distinguish nonfavorable responders early in the course of treatment and assist in monitoring for disease progression.

SdiA, an Escherichia coli homologue of quorum-sensing regulators, controls the expression of virulence factors in enterohaemorrhagic Escherichia coli O157:H7.

The quorum-sensing system in bacteria is a well-known regulatory system that controls gene expression in a cell density-dependent manner. A transcriptional regulator (LuxR homologue), signal synthase (LuxI homologue) and autoinducer (acyl homoserine lactone) are indispensable for this system in most Gram-negative bacteria. In this study, we found that SdiA, an Escherichia coli LuxR homologue, is a negative regulator of the expression of virulence factors EspD and intimin in enterohaemorrhagic E. coli (EHEC) O157:H7. The expression of EspD and intimin was inhibited at the RNA level upon SdiA overexpression. SdiA has a DNA-binding motif in its C-terminal part and can bind to the promoter regions of the esp and eae genes in vitro. Extracellular factors, which accumulate in culture supernatants of O157:H7 at the stationary phase of growth and inhibit EspD and intimin synthesis, bind to the N-terminal part of SdiA in vivo and in vitro. O157:H7 overproducing the N-terminal part of SdiA exhibited hypertranscription of EspD and intimin, suggesting that the overproduced N-terminal part had inhibited the activity of intact SdiA through titration of the extracellular factors. These results indicate that a quorum-sensing system including the SdiA protein controls colonization by O157:H7.

Gasless, hand-assisted retroperitoneoscopic nephroureterectomy for urothelial cancer of the upper urinary tract.

We report our initial experiences with gasless, hand-assisted retroperitoneoscopic nephroureterectomy for the treatment of urothelial cancer of the upper urinary tract. One hand was inserted by way of the small incision made in the lower abdomen. This method provides easy maneuverability and an acceptable operative time without opening the upper urinary tract.