Targeted disruption of the mouse prosaposin gene affects the development of the prostate gland and other male reproductive organs

The prosaposin gene encodes a 65-70 kilodalton (kd) protein, which is secreted or targeted to lysosomes. In lysosomes, prosaposin is the precursor of 4 activator proteins, designated saposins A, B, C, and D, which promote by acidic hydrolases, the degradation of glycosphingolipids with short oligosaccharide chains. Mutations of the prosaposin gene have been linked to several lysosomal storage disorders. An animal model was recently developed by creating a null allele in embryonic stem cells through gene targeting in order to investigate the phenotypic diversity of prosaposin mutations, the involvement of this protein in lysosomal storage diseases, and to develop potential therapeutic approaches. Mutant homozygous mice die at 35-40 days of age and neurological disorders contribute to their early death. Secreted prosaposin is present in milk and in cerebrospinal and seminal fluids. In the nervous system, prosaposin exhibits a trophic activity. Examination of reproduc-tive organs in homozygous mutant males shows several abnormalities such as a decrease in testis size with reduced spermiogenesis, and an involution of the prostate, seminal vesicle, and epididymis, although levels of testosterone in blood remain normal. In the prostate of homozygous mutants, only basal cells appear to be present, whereas secretory cells are absent. The epithelia in efferent ducts is formed by ciliated cells, whereas heterozygotes exhibit a majority of nonciliated cells. Our data indicate that prosaposin is involved in the development and maintenance of male reproductive organs. In prostatic epithelium, targeted disruption of the prosaposin gene appears to inactivate the mitogen-activated protein kinase pathway and to interfere with differentiation of secretory cells.     

Cisplatin plus gemcitabine versus a cisplatin-based triplet versus nonplatinum sequential doublets in advanced non-small-cell lung cancer: a Spanish Lung Cancer Group phase III randomized trial.

PURPOSE: To compare the survival benefit obtained with cisplatin plus gemcitabine, a cisplatin-based triplet, and nonplatinum sequential doublets in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Stage IIIB to IV NSCLC patients were randomly assigned to receive cisplatin 100 mg/m2 day 1 plus gemcitabine 1,250 mg/m2 days 1 and 8, every 3 weeks for six cycles (CG); cisplatin 100 mg/m2 day 1 plus gemcitabine 1,000 mg/m2 and vinorelbine 25 mg/m2 days 1 and 8, every 3 weeks for six cycles (CGV); or gemcitabine 1,000 mg/m2 plus vinorelbine 30 mg/m2 days 1 and 8, every 3 weeks for three cycles, followed by vinorelbine 30 mg/m2 days 1 and 8 plus ifosfamide 3 g/m2 day 1, every 3 weeks for three cycles (GV-VI). RESULTS: Five hundred fifty-seven patients were assigned to treatment (182 CG, 188 CGV, 187 GV-VI). Response rates were significantly inferior for the nonplatinum sequential doublet (CG, 42%; CGV, 41%; GV-VI, 27%; CG v GV-VI, P =.003). No differences in median survival or time to progression were observed. Toxicity was higher for the triplet: grade 3 to 4 neutropenia (GC, 32%; CGV, 57%; GV-VI, 27%; P <.05); neutropenic fever (CG, 4%; CGV, 19%; GV-VI, 5%; P <.0001); grade 3 to 4 thrombocytopenia (CG, 19%; CGV, 23%; GV-VI, 3%; P =.0001); and grade 3 to 4 emesis (GC, 22%; GCV, 32%; GV-VI, 6%; P <.0001). CONCLUSION: On the basis of these results, CG remains a standard regimen for first-line treatment of advanced NSCLC.     

Influence of obesity on the appearance of proteinuria and renal insufficiency after unilateral nephrectomy

BACKGROUND: Some patients develop proteinuria and progressive renal failure after unilateral nephrectomy, although the majority of patients maintain normal renal function. Reasons to explain this different evolution are not known. METHODS: A cross-sectional study was performed in 73 patients who had undergone unilateral nephrectomy 13.6 +/- 8.6 years before. Patients with morphologic abnormalities in the remaining kidney, systemic disorders, or abnormal renal function at the time of nephrectomy were excluded. All of the 73 included patients showed normal renal function and negative proteinuria at nephrectomy. The patient's medical records were reviewed, and clinical and analytical data throughout follow-up were obtained. RESULTS: Fifty-three out of the 73 patients (group I) showed a normal renal function and negative proteinuria at the cross-sectional study. The remaining 20 patients (group II) showed proteinuria (3.4 +/- 3.1 g/day). The time elapsed between nephrectomy and proteinuria appearance was 10.1 +/- 6.1 years. Thirteen patients of group II had developed renal insufficiency (serum creatinine at the cross-sectional study of 3.9 + 3.2 mg/dL) in addition to proteinuria. The time elapsed between proteinuria appearance and the onset of renal insufficiency was 4.1 +/- 4.3 years. Renal insufficiency showed a slowly progressive course in most of these patients. There were no significant differences between group I and group II patients in age, gender, renal function, or blood pressure at the time of nephrectomy. In contrast, group II patients showed a body mass index (BMI) that was significantly higher than group I at nephrectomy (31.6 +/- 5.6 vs. 24.3 +/- 3.7 kg/m(2), P < 0.001), at cross-sectional study (33.3 +/- 6.6 vs. 25.1 +/- 3.5 kg/m(2), P < 0.001), and throughout follow-up. Among the 14 obese (BMI > 30 kg/m(2)) patients at the time of nephrectomy, 13 (92%) developed proteinuria/renal insufficiency. In contrast, among the 59 patients with BMI < 30 kg/m(2), only 7 (12%) developed these complications (P < 0.001). Kaplan-Meier estimated probability of negative proteinuria and normal renal function 10 years after nephrectomy was 40 and 70%, respectively, in obese patients at nephrectomy. At 20 years after nephrectomy, these percentages were 8 and 35%, respectively. In contrast, in nonobese patients, the probability of negative proteinuria and normal renal function was 93 and 98%, respectively, at 10 years (P < 0.001) and 77 and 91%, respectively, at 20 years (P < 0.001). Multiple logistic regression analysis showed that the risk of developing renal disease was only statistically correlated with BMI at the time of unilateral nephrectomy (odds ratio 1.34, 1.03 to 1.76 CI). CONCLUSIONS: Obese patients are at risk for developing proteinuria and chronic renal failure after unilateral nephrectomy. Regular and long-term follow-up are recommended in these patients.     

The value of intraoperative cystoscopy in urogynecologic and reconstructive pelvic surgery

OBJECTIVE: Our goal was to evaluate the role of intraoperative cystoscopy during surgery for pelvic organ prolapse and urinary incontinence. STUDY DESIGN: Charts of 224 consecutive patients who had intraoperative cystoscopy performed after urogynecologic surgery were reviewed. RESULTS: Nine injuries occurred that were unsuspected before cystoscopy, for an incidence of 4%. Six ureteral ligations occurred, four after Burch cystourethropexy and two after vaginal culdoplasty. Intravesical sutures were noted after two Burch procedures, and another injury occurred with passage of fascia lata through the bladder during a pubovaginal sling procedure. Eight injuries were managed by removal and replacement of the suture or sling with only one requiring ureteroneocystotomy. When patients with injuries were compared with those without, there were no statistical differences in demographic or surgical parameters. CONCLUSIONS: The potential for damage to the lower urinary tract is significant with complex urogynecologic surgery. Because of the increased and delayed morbidity associated with unrecognized injury, intraoperative surveillance cystoscopy should be considered a part of all such procedures.(Am J Obstet Gynecol 1997;177:71)     

Effect of Dexamethasone Therapy on the Neonatal Ductus Arteriosus

Patent ductus arteriosus (PDA) is believed to be a contributing factor in the etiopathogenesis of bronchopulmonary dysplasia (BPD). We studied the effects of early dexamethasone therapy on persistent ductal patency and the role of PDA in the etiopathogenesis of BPD during the course of a randomized double-blind trial of dexamethasone to prevent BPD. Infants, who weighed between 700 and 999 g, had severe RDS, and had been given surfactant, were randomized to receive a 12-day course of dexamethasone (n= 13) or placebo (n= 17) starting within the first 12 hours of postnatal life. The diagnosis of PDA was made clinically and was confirmed by cardiac ultrasound. The incidence of clinically significant ductus in infants who weighed less than 1000 g was 23% in the dexamethasone-treated group, as compared with 59% in infants who were given placebo. This difference was marginally significant, p= 0.05, odds ratio 0.21, 95% confidence interval 0.04–1.05. None of the infants in the dexamethasone group had recurrence of PDA after indomethacin therapy as compared with three infants in the placebo group. Dexamethasone significantly reduced the number of days infants required ventilator and supplemental oxygen as compared with infants who received placebo. Dexamethasone, as compared with placebo, also reduced the incidence of BPD, p= 0.025, odds ratio 0.08, 95% confidence interval 0.01–0.58. Dexamethasone may reduce the incidence of PDA in premature infants who weigh less than 1000 g at birth and thereby reduce the incidence of BPD.     

Tamoxifen aziridine binding to cytosolic proteins from human breast specimens is negatively associated with estrogen receptors, progesterone receptors, pS2, and cathepsin-D

[³H]Tamoxifen Aziridine ([³H]TAZ) is a derivative of the antiestrogen tamoxifen that covalently labels the Estrogen Receptor (ER), and perhaps other uncharacterized proteins. In a previous article we described that [³H]TAZ binds to a cytosolic protein from human uterine tissues that shares some, but not all, the ER properties. Here we have extended these studies to [³H]TAZ binding to cytosol proteins from human breast cancer specimens, and studied its quantitative association with other molecular markers and clinico-pathological variables. Cytosols were obtained in hypotonic buffer containing 20 mM molybdate and protease inhibitors, incubated with [³H]TAZ, and subjected to Sucrose Gradient Analysis (SGA). A [³H]TAZ labeled peak that consistently migrated with the 4S fractions was found in most of the assayed cytosols (range of 0 to 1278 fmol/mg p.). The 4S peak of [³H]TAZ was partially inhibited by both estrogens and antiestrogens. When [³H]E₂ was used instead of [³H]TAZ, only an 8S peak was detected. [³H]TAZ was covalently bound to a protein with an apparent MW of 65 kDa, as determined by SDS-PAGE and fluorography. The mean of [³H]TAZ binding was significantly higher in the subgroups of samples classified as ER-, PR-, pS2- or cathepsin D-, than in the respective positive subgroups (P < 0.01 in all the cases). [³H]TAZ binding was not associated with clinico-pathological variables, except that its mean was significantly larger in tumors larger than 5 cm than in smaller tumors. These results, and those previously reported, suggest that: 1) [³H]TAZ labels a cytosolic protein present in human breast cancers and uterine tissues that does not share all the ER properties, and 2) the [³H]TAZ binding by breast cancer cytosols is negatively associated with markers of estrogenic dependency, and its quantification may provide valuable information on antiestrogen responsiveness of a given tumor.     

Visual inspection with acetic acid for cervical cancer screening outside of low-resource settings.

OBJECTIVES: To assess visual inspection with acetic acid (VIA) as a screening tool for use in a well-equipped health center in Peru, to evaluate VIA as an alternative or adjunct to the Papanicolaou (Pap) smear, and to determine if VIA can play a role in settings other than low-resource ones. METHODS: This was a prospective study of 1 921 asymptomatic women living in Lima, Peru, carried out in 1999 and 2000. The study was performed at a cancer center equipped with the latest-generation technology and highly trained oncologists. The women underwent a complete clinical evaluation, including a Pap smear and VIA. Participants with any positive test were referred for colposcopy and biopsy. RESULTS: More women tested positive by VIA than on the Pap smear (6.9% vs. 4.2%; P = 0.0001). There were 35 women with histologic cervical intraepithelial neoplasia grade 1 (CIN 1); of these, 15 were detected by Pap and 20 by VIA (P = 0.4). A diagnosis of CIN 2 or 3 (CIN 2-3) was confirmed in a total of 13 cases; Pap detected 5 of the cases and VIA 11 of the cases (P = 0.06). The positive predictive value for detection of CIN 2+ was 8.3% for VIA and 6.3% for Pap (P = 0.5). Most importantly, while only 2.3% of patients with a positive VIA were lost to follow-up before colposcopy, that was true for 26.3% of the women with a positive Pap smear (P < 0.0001). CONCLUSIONS: VIA is useful for detection of precursor lesions of cervical cancer not only in low-resource settings but also in well-equipped health centers and cancer centers. In these non-low-resource settings, VIA has a positive predictive value comparable to the conventional Pap smear, but it is more likely to achieve earlier diagnosis, follow-up, and treatment than cytology-based screening.     

Estimation of the dietary intake of cadmium, lead, mercury, and arsenic by the population of Santiago (Chile) using a Total Diet Study.

Dietary intake of arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb) by the population of Santiago (Chile) was determined using a Total Diet Study in the market basket modality. After conducting a survey of the foods consumed in the last 24 h, the most consumed food products were included in the basket. Subsequently, they were cooked or prepared according to typical Chilean procedures and grouped into 17 food categories according to their chemical characteristics. The fish and shellfish group had the highest contents of As (1351 ng/g wet weight, ww), Cd (277 ng/g ww), and Hg (48 ng/g ww), while the sugar group had the highest content of Pb (251 ng/g ww). For a person with a body weight of 68 kg, the dietary intakes of As (77 microg/day), Cd (20 microg/day), Hg (5 microg/day), and Pb (206 microg/day) are lower than the provisional tolerable weekly intake values established by the FAO/WHO. Consequently, the total intakes of As, Cd, Hg, and Pb in Santiago (Chile) are within the limits estimated as safe.