Prognostic factors affecting long-term outcomes in patients with resected stage IIIA pN2 non-small-cell lung cancer: 5-year follow-up of a phase II study

The aim was to investigate the efficacy of neoadjuvant docetaxel-cisplatin and identify prognostic factors for outcome in locally advanced stage IIIA (pN2 by mediastinoscopy) non-small-cell lung cancer (NSCLC) patients. In all, 75 patients (from 90 enrolled) underwent tumour resection after three 3-week cycles of docetaxel 85 mg m-2 (day 1) plus cisplatin 40 or 50 mg m-2 (days 1 and 2). Therapy was well tolerated (overall grade 3 toxicity occurred in 48% patients; no grade 4 nonhaematological toxicity was reported), with no observed late toxicities. Median overall survival (OS) and event-free survival (EFS) times were 35 and 15 months, respectively, in the 75 patients who underwent surgery; corresponding figures for all 90 patients enrolled were 28 and 12 months. At 3 years after initiating trial therapy, 27 out of 75 patients (36%) were alive and tumour free. At 5-year follow-up, 60 and 65% of patients had local relapse and distant metastases, respectively. The most common sites of distant metastases were the lung (24%) and brain (17%). Factors associated with OS, EFS and risk of local relapse and distant metastases were complete tumour resection and chemotherapy activity (clinical response, pathologic response, mediastinal downstaging). Neoadjuvant docetaxel-cisplatin was effective and tolerable in stage IIIA pN2 NSCLC, with chemotherapy contributing significantly to outcomes.

Oral misoprostol for third stage of labor: a randomized placebo-controlled trial

OBJECTIVE: To investigate whether orally administered misoprostol during the third stage of labor is efficient in reducing postpartum blood loss. METHODS: In a double-masked trial, during vaginal delivery women were randomly assigned to receive a single oral dose of misoprostol (600 microg) or placebo in third stage of labor, immediately after cord clamping. The third stage of labor was managed routinely by early cord clamping and controlled cord traction; oxytocin was administered only if blood loss seemed more than usual. Blood loss was estimated by the delivering physician and differences in hematocrit were measured before and after delivery. RESULTS: Mean (+/- standard error of the mean) estimated blood loss (345 +/- 19.5 mL versus 417 +/- 25.9 mL, P = .031) and hematocrit difference (4.5 +/- 0.9% versus 7.9 +/- 1.2%, P = .014) were significantly lower in women who received misoprostol than those who received placebo. Fewer women in the misoprostol group had postpartum hemorrhage (blood loss of at least 500 mL), but that difference was not statistically significant (7% versus 15%, P = .43). Additional oxytocin before or after placental separation was used less often in the misoprostol group (16% versus 38%, P = .047). There were no differences in the length of third stage of labor (8 +/- 0.9 minutes versus 9 +/- 1 minutes, P = .947). There were no differences in pain during third stage of labor, postpartum fever, or diarrhea, but shivering was more frequent in the misoprostol group. CONCLUSION: Oral misoprostol administered in the third stage of labor reduced postpartum blood loss and might be effective in reducing incidence of postpartum hemorrhage.

AN OVERVIEW OF OBSERVATIONAL SLEEP RESEARCH WITH APPLICATION TO SLEEP STAGE TRANSITIONING

In this manuscript we give an overview of observational sleep research with a particular emphasis on sleep stage transitions. Sleep states represent a categorization of sleep electroencephalogram behavior over the night. We postulate that the rate of transitioning between sleep states is an important predictor of health. This claim is evaluated by comparing subjects with sleep disordered breathing to matched controls.

Plasma S-nitrosothiol status in neonatal calves: ontogenetic associations with tissue-specific S-nitrosylation and nitric oxide synthase

Neonatal cattle and in part neonates of other species have manyfold higher plasma concentrations of nitrite plus nitrate than mature cows and subjects of other species, suggesting an enhanced and needed activation of the nitric oxide (NO) axis at birth. While the biological half-life of NO is short (<1 sec), its functionality can be prolonged, and in many regards more discretely modulated, when it reacts with low-molecular-weight and protein-bound thiols to form S-nitrosothiols (RSNO), from which NO subsequently can be rereleased. We used the calf as a model to test the hypothesis that plasma concentrations of RSNO are elevated at birth in mammals, correlate with ascorbate and urate levels, are selectively generated in critical tissue beds, and are generated in a manner temporally coincident with changes in tissue levels of active NO synthases (NOS). Plasma concentrations of RSNO, ascorbate, and urate were highest immediately after birth (Day 0), dropped >50% on Day 1, and gradually decreased over time, reaching a nadir in mature cattle. Albumin and immunoglobulin G were identified as major plasma RSNO. The presence of S-nitrosocysteine (SNC, a validated marker for S-nitrosylated proteins), inducible NOS (iNOS), and activated endothelial NOS (eNOS phosphorylated at Ser1177) in different tissues was analyzed by immunohistochemistry in another group of similar-aged calves. SNC, iNOS, and phosphorylated eNOS were detected in liver and ileum at the earliest timepoint of sampling (4 hrs after birth), increased between 4 and 24 hrs, and then declined to near-nondetectable levels by 2 weeks of life. Our data show that the neonatal period in the bovine species is characterized by highly elevated and coordinated NO-generating and nitrosylation events, with the ontogenetic changes occurring in iNOS and eNOS contents in key tissues as well as RSNO products and associated antioxidant markers.

The synergistic action of a VEGF-receptor tyrosine-kinase inhibitor and a sensitizing PDGF-receptor blocker depends upon the stage of vascular maturation

OBJECTIVE: To investigate the effects of tyrosine-kinase inhibitors of vascular endothelial growth factor (VECF) and platelet-derived growth factor (PDCF)-receptors on non-malignant tissue and whether they depend upon the stage of vascular maturation. MATERIALS AND METHODS: PTK787/ZK222584 and CGP53716 (VEGF- and PDGF-receptor inhibitor respectively), both alone and combined, were applied on chicken chorioallantoic membrane (CAM). RESULTS: On embryonic day of CAM development (E)8, only immature microvessels, which lack coverage of pericytes, are present: whereas the microvessels on E12 have pericytic coverage. This development was reflected in the expression levels of pericytic markers (alpha-smooth muscle actin, PDGF-receptor beta and desmin), which were found by immunoblotting to progressively increase between E8 and E12. Monotherapy with 2 microg of PTK787/ZK222584 induced significant vasodegeneration on E8, but not on E12. Monotherapy with CGP53716 affected only pericytes. When CGP53716 was applied prior to treatment with 2 microg of PTK787/ZK222584, vasodegeneration occurred also on E12. The combined treatment increased the apoptotic rate. as evidenced by the cDNA levels of caspase-9 and the TUNEL-assay. CONCLUSION: Anti-angiogenic treatment strategies for non-neoplastic disorders should aim to interfere with the maturation stage of the target vessels: monotherapy with VEGF-receptor inhibitor for immature vessels, and combined anti-angiogenic treatment for well developed mature vasculature.

A family of stage-specific alanine-rich proteins on the surface of epimastigote forms of Trypanosoma brucei

A 'two coat' model of the life cycle of Trypanosoma brucei has prevailed for more than 15 years. Metacyclic forms transmitted by infected tsetse flies and mammalian bloodstream forms are covered by variant surface glycoproteins. All other life cycle stages were believed to have a procyclin coat, until it was shown recently that epimastigote forms in tsetse salivary glands express procyclin mRNAs without translating them. As epimastigote forms cannot be cultured, a procedure was devised to compare the transcriptomes of parasites in different fly tissues. Transcripts encoding a family of glycosylphosphatidyl inositol-anchored proteins, BARPs (previously called bloodstream alanine-rich proteins), were 20-fold more abundant in salivary gland than midgut (procyclic) trypanosomes. Anti-BARP antisera reacted strongly and exclusively with salivary gland parasites and a BARP 3' flanking region directed epimastigote-specific expression of reporter genes in the fly, but inhibited expression in bloodstream and procyclic forms. In contrast to an earlier report, we could not detect BARPs in bloodstream forms. We propose that BARPs form a stage-specific coat for epimastigote forms and suggest renaming them brucei alanine-rich proteins.

Stability measurements of 1-stage implants in the edentulous mandible by means of resonance frequency analysis

OBJECTIVE: Resonance frequency analysis (RFA) is a method of measuring implant stability. However, little is known about RFA of implants with long loading periods. The objective of the present study was to determine standard implant stability quotients (ISQs) for clinical successfully osseointegrated 1-stage implants in the edentulous mandible. MATERIALS AND METHODS: Stability measurements by means of RFA were performed in regularly followed patients who had received 1- stage implants for overdenture support. The time interval between implant placement and measurement ranged from 1 year up to 10 years. The short-term group comprised patients who were followed up to 5 years, while the long-term group included patients with an observation time of > 5 years up to 10 years. For further comparison RFA measurements were performed in a matching group with unloaded implants at the end of the surgical procedure. For statistical analysis various parameters that might influence the ISQs of loaded implants were included, and a mixed-effects model applied (regression analysis, P <.0125). RESULTS: Ninety-four patients were available with a total of 205 loaded implants, and 16 patients with 36 implants immediately after the surgical procedure. The mean ISQ of all measured implants was 64.5 +/- 7.9 (range, 58 to 72). Statistical analysis did not reveal significant differences in the mean ISQ related to the observation time. The parameters with overall statistical significance were the diameter of the implants and changes in the attachment level. In the short-term group, the gender and the clinically measured attachment level had a significant effect. Implant diameter had a significant effect in the long-term group. CONCLUSIONS: A mean ISQ of 64.5 +/- 7.9 was found to be representative for stable asymptomatic interforaminal implants measured by the RFA instrument at any given time point. No significant differences in ISQ values were found between implants with different postsurgical time intervals. Implant diameter appears to influence the ISQ of interforaminal implants.

Long-term followup results of 1 cycle of adjuvant bleomycin, etoposide and cisplatin chemotherapy for high risk clinical stage I nonseminomatous germ cell tumors of the testis

PURPOSE: We evaluated the long-term outcome after 1 cycle of adjuvant modified bleomycin, etoposide and cisplatin chemotherapy in patients who underwent orchiectomy for high risk clinical stage I nonseminomatous germ cell tumor of the testis. MATERIALS AND METHODS: Between 1995 and 1999 a consecutive series of 44 patients underwent orchiectomy for clinical stage I nonseminomatous germ cell tumor of the testis, followed by a single postoperative cycle of adjuvant modified bleomycin, etoposide and cisplatin for vascular or lymphatic tumor invasion, and/or a predominance (50% or greater) of embryonal carcinoma. RESULTS: Four of the 44 patients were excluded from analysis. Of the patients 35 had no evidence of disease at a median followup of 99 months (range 60 to 134). One patient with progression after 13 months showed complete remission after 3 cycles of salvage bleomycin, etoposide and cisplatin chemotherapy but he died of pneumonia 4 weeks after the third course. Two patients underwent orchiectomy for contralateral testis cancer at 18 and 42 months, respectively, followed by an additional 3 cycles of adjuvant chemotherapy. They remained relapse-free for 4 and 92 months, respectively. The former patient was lost to followup after 4 months. Two other patients were disease-free at 10 and 31 months, respectively, and were lost to followup thereafter. Late side effects were tinnitus in 3 patients and involuntary childlessness in 3, of whom 2 had cryptorchidism of the contralateral testis. Nine patients fathered children. CONCLUSIONS: One cycle of bleomycin, etoposide and cisplatin effectively decreases the risk of relapse in patients with high risk stage I nonseminomatous germ cell tumor of the testis. It has minimal side effects and can be a valuable alternative to retroperitoneal lymph node dissection.