Overexpression of laminin-5 gamma2 chain and its prognostic significance in urothelial carcinoma of urinary bladder: association with expression of cyclooxygenase 2, epidermal growth factor receptor [corrected] and human epidermal growth factor receptor [corrected] 2

Laminin-5 (LN-5) and cyclooxygenase 2 (COX-2) play important roles in many kinds of cancers. Recently, it has been reported that epidermal growth factor receptor [corrected] (EGFR) and/or human epidermal growth factor receptor [corrected] 2 (HER2) expressions are associated with LN-5 and/or COX-2 expressions in a few carcinoma cell lines and human tumor tissue. LN-5, COX-2, EGFR, and HER2 expressions were examined immunohistochemically in 67 patients with urothelial carcinomas (UCs), and associations among these 4 biomarkers and clinicopathologic characteristics were investigated. Patients were classified into transurethral resection group and cystectomy group based on clinical end points, and prognostic significances of increased expressions were evaluated. Overexpression of LN-5, COX-2, EGFR, and HER2 was observed in 16 (23.9%), 34 (50.7%), 42 (62.7%), and 15 (22.4%) of 67 patients, respectively. LN-5 overexpression was associated high-grade (P = .002), invasive (pTa+1 versus pT2-4, P = .011), and nonpapillary (P = .027) UCs. Concerning EGFR and HER2, high-grade (EGFR, P = .0009; HER2, P = .003) and nonpapillary (EGFR, P = .016; HER2, P = .0002) UCs had a significantly higher overexpression rate. UCs penetrating basal membrane (pT1-4) showed significantly higher overexpression rates than pTa UCs on all biomarkers. In transurethral resection group, LN-5 overexpression could be proved as an independent prognostic parameter for intravesical recurrence (P = .007), whereas in cystectomy group, nodal involvement was an independent prognostic parameter for cause-specific survival (P = .025). The current study showed that the 4 biomarkers were associated with aggressive behaviors of UCs. Above all, LN-5 overexpression was considered to play an important role in intravesical recurrence of superficial UCs.     

Family experience with palliative sedation therapy for terminally ill cancer patients

Symptomatic sedation is often required in terminally ill cancer patients, and could cause significant distress to their family. The aims of this study were to clarify the family experience during palliative sedation therapy, including their satisfaction and distress levels, and the determinants of family dissatisfaction and high-level distress. A multicenter questionnaire survey assessed 280 bereaved families of cancer patients who received sedation in 7 palliative care units in Japan. A total of 185 responses were analyzed (response rate, 73%). The families reported that 69% of the patients were considerably or very distressed before sedation. Fifty-five percent of the patients expressed an explicit wish for sedation, and 89% of families were clearly informed. Overall, 78% of the families were satisfied with the treatment, whereas 25% expressed a high level of emotional distress. The independent determinants of low levels of family satisfaction were: poor symptom palliation after sedation, insufficient information-giving, concerns that sedation might shorten the patient's life, and feelings that there might be other ways to achieve symptom relief. The independent determinants of high levels of family distress were: poor symptom palliation after sedation, feeling the burden of responsibility for the decision, feeling unprepared for changes in the patient's condition, feeling that the physicians and nurses were not sufficiently compassionate, and shorter interval to patient death. Palliative sedation therapy was principally performed to relieve severe suffering based on family and patient consent. Although the majority of families were comfortable with this practice, clinicians should minimize family distress by regular monitoring of patient distress and timely modification of sedation protocols, providing sufficient information, sharing the responsibility of the decision, facilitating grief, and providing emotional support.     

Clinical study of flavor disturbance

OBJECTIVE: We have observed that, in cases of smell loss, patients often complain of taste loss as well even though they actually have normal gustatory acuity according to gustatory tests; we have defined such symptoms as "flavor disturbance". The clinical features of flavor disturbance are reported in this paper. MATERIAL AND METHODS: A total of 297 patients (99 males, 198 females; mean age 55.5 years) were treated for olfactory disturbance at the hospital of Hyogo College of Medicine between July 1995 and August 2001. Sixty-six out of 297 patients (22.5%) also experienced taste disturbance, and 49 of these 66 cases were evaluated by means of smell and taste tests. These 49 patients who complained of taste and smell loss were classified into two groups according to the results of their smell and taste tests. Patients who only complained of olfactory disturbance were also reviewed. RESULTS: There was no relationship between the severity of olfactory disturbance and the degree of flavor disturbance. The incidence of flavor disturbance was high in patients with sudden olfactory disturbance after upper respiratory tract infection or head trauma and low in those with slowly progressive olfactory disturbance. The symptoms of flavor disturbance improved regardless of whether smell was improved or not. CONCLUSIONS: The patients with flavor disturbance tended to misrecognize that they had taste loss because of sudden smell loss, and there were more of these cases than we expected. When patients with smell and taste loss are treated, flavor disturbance should also be considered.     

Anatomical features of periprostatic tissue and its surroundings: a histological analysis of 79 radical retropubic prostatectomy specimens

BACKGROUND: A proper understanding of prostatic and periprostatic anatomy is essential for surgical procedures and pathological diagnosis; however, the detailed features have not been commonly investigated and completely understood. METHODS: Seventy-nine non-nerve-sparing radical prostatectomy specimens were microscopically investigated for Denonvilliers' fascia, lateral pelvic fascia, prostatic capsule, anterior fibromuscular stroma and the neurovascular bundle. RESULTS: At the lateral aspect, the lateral pelvic fascia and the prostatic capsule were separated by adipose tissue in 41 cases (52%), whereas they adhered in 38 cases (48%). In only 41 cases (52%), the neurovascular bundle existed locally at the postero-lateral region with definite 'bundle' formations. Denonvilliers' fascia and the prostatic capsule adhered tightly at the center of the posterior aspect in 77 cases (97%). A smooth transition from the prostatic capsule to the anterior fibromuscular stroma was observed in all cases. In 70 cases (89%), no prostatic capsule was independently recognized at the anterior aspect. In the remaining 9 cases (11%), the capsule was recognizable as distinct from the anterior fibromuscular stroma. In 67 cases (85%), the lateral pelvic fascia connected and fused with the anterior fibromuscular stroma, and covered the outermost regions of the lateral and anterior surfaces. CONCLUSIONS: All the periprostatic structures are closely related and influence each other. The results support the rationale of anatomical radical prostatectomy, and should be taken into consideration for surgical procedures and pathological diagnosis.     

Synthetic decarboxylated S-adenosyl-L-methionine as a substrate for aminopropyl transferases

Synthetic decarboxylated S-adenosyl-L-methionine (dcAdoMet), a mixture of the absolute configuration of S and R at the sulfonium center, was evaluated as a substrate for the measurement of spermidine synthase activity. The diastereomers were separated by HPLC with an isocratic elution, and the constant for racemization at the sulfur was determined to be 2.4x10(-6) s(-1) at 37 degrees C and pH 1.5 for the first-eluted biologically active isomer (S-dcAdoMet) and 2.0x10(-6) s(-1) for the second-eluted biologically inactive isomer (R-dcAdoMet). The peak area ratio of S-dcAdoMet to R-dcAdoMet of 48 to 52 in HPLC supported the different racemization constants. Similar substrate activity of dcAdoMet to that of S-dcAdoMet was demonstrated by enzymatic spermidine synthesis. It was shown from the result that the racemized [methyl-(14)C]dcAdoMet prepared in this report was useful for measuring spermidine synthase activity.     

Chymase inhibitor improves survival in hamsters with myocardial infarction

The purpose of the present study was to assess the effects of chronic treatment with an orally active chymase inhibitor, 4-[1-(naphthylmethyl)benzimidazol-2-ylthio]butanoic acid (TEI-E548), in a hamster myocardial infarction model. In the first experiment, after confirming the biochemical inhibitory action of TEI-E548 on human and hamster chymases (Ki = 6.2 and 30.6 nM, respectively), the biological action of TEI-E548 in vivo was assessed by the inhibition of hamster chymase-induced microvascular leakage. In the second experiment, myocardial infarction was produced by coronary artery ligation in male Syrian hamsters. TEI-E548 (0.1% containing chow) was given 24 h after surgery and continued for 3 or 5 weeks, while the control and sham-operated groups were fed a standard chow. The survival rate was assessed in each group. At the end of each study period, blood pressure was measured at the left hind-limb, the heart rate and cardiac function were measured by echocardiography, the end-diastolic pressure by a direct catheterization, and organ weights and biochemical parameters, including plasma renin and angiotensin-converting enzyme activities and plasma angiotensin I and angiotensin II concentrations, were measured. In the first experiment, a standard chow containing 0.1% TEI-E548 completely inhibited the hamster chymase-induced microvascular leakage. In the second experiment, TEI-E548 treatment significantly increased the survival rate (37% versus control), and attenuated cardiac hypertrophy (13% versus control) and end-diastolic left ventricular pressure (34% versus control), but it did not decrease the infarction size nor improve the ejection fraction. The plasma angiotensin II concentration post-myocardial infarction was significantly suppressed by TEI-E548 throughout the study period. We conclude that TEI-E548 is an orally active useful chymase inhibitor and improves survival and cardiac hypertrophy of the post-myocardial infarction hamster.     

Discovery of novel N-phenylglycine derivatives as potent and selective beta(3)-adrenoceptor agonists for the treatment of frequent urination and urinary incontinence

With a novel assay using isolated ferret detrusor to estimate beta(3)-adrenoceptor agonistic activity, we found that a series of glycine derivatives of ritodrine, a beta(2)-adrenoceptor agonist, are potent beta(3)-adrenoceptor agonists, with excellent selectivity versus beta(1) and beta(2) subtypes. Substitution of halogens in the phenyl ring increased potency and selectivity for the beta(3)-adrenoceptor, and this was dependent upon the position of the halogens. The chlorine-substituted derivatives 3f-i exhibited potent beta(3)-adrenoceptor-mediated relaxation of ferret detrusor (EC(50) = 0.93, 11, 14, and 160 nM) and higher potency at beta(3)-adrenoceptors than at beta(1) or beta(2). The intravenous administration of 3h significantly reduced the urinary bladder pressure in anesthetized male rats (ED(50) = 48 microg/kg) without cardiovascular side effects. This article is the first report of structure-activity relationships (SAR) concerning beta(3)-adrenoceptor agonists as agents for the treatment of urinary frequency and incontinence.