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We demonstrate high power (multiwatt) low noise single frequency operation of tunable compact verical-external- cavity surface-emitting-lasers exhibiting a low divergence high beam quality, of great interest for photonics applications. The quantum-well based lasers are operating in CW at RT at 1m and 2.3m exploiting GaAs and Sb technologies. For heat management purpose the VECSEL membranes were bonded on a SiC substrate. Both high power diode pumping (using GaAs commercial diode) at large incidence angle and electrical pumping are developed. The design and physical properties of the coherent wave are presented. We took advantage of thermal lens-based stability to develop a short (0.5 < 5mm) external cavity without any intracavity filter. We measured a low divergence circular TEM00 beam (M2= 1.2) close to diffraction limit, with a linear light polarization (> 30 dB). The side mode suppression ratio is > 45 dB. The free running laser linewidth is 37 kHz limited by pump induced thermal fluctuations. Thanks to this high-Q external cavity approach, the frequency noise is low and the dynamics is in the relaxation-oscillation-free regime, exhibiting low intensity noise (< 0.1%), with a cutoff frequency > 41MHz above which the shot noise level is reached. The key parameters limiting the laser power and coherence will be discussed. These design/properties can be extended to other wavelengths.

No relevant conflicts of interest to declare.

Several blood pressure (BP) and autonomic abnormalities have been associated with pregnancy-induced hypertension (PIH) but no noninvasive method has been identified as able to predict the development of PIH. In the present study we examined prospectively 45 consecutive normotensive pregnant women aged 29.9 + 3.3 years at 27 + 4 gestational week, referred to an institutional tertiary care referral center for known risk factors for developing PIH: pre-eclampsia and/or intrauterine growth retardation in previous pregnancy, or abnormal laboratory tests in present pregnancy (hypocalcemia, hyperuricemia). The following tests were performed: echo-Doppler of uterine arteries to evaluate utero-placental resistance index (URI), ambulatory blood pressure monitoring (ABPM) to measure the systolic and diastolic MESOR (Midline Estimating Statistic of Rhythm) defined as the average value of the rhythmic function fitted to the blood pressure data, cardiovascular tests to evaluate the autonomic nervous function (Valsalva manoeuvre, deep breathing test, lying-to-standing test, cold pressor test, isometric handgrip, and power spectral analysis of heart rate variability). Unpaired t test was used to evaluate differences between normotensive and hypertensive women. The logistic regression model with backward selection was used to estimate the probability of PIH. Eighteen women (40 %) developed gestational hypertension. Compared to normotensives, women who developed PIH showed higher systolic (120 ± 6 vs. 114 ± 8 mm Hg respectively; p<0.05) and diastolic MESOR (75 ± 4 vs. 68 ± 5 mm Hg respectively; p< 0.001). The systolic response to Valsalva manoeuvre was significantly increased in women who developed PIH with respect to normotensives (35 ± 10 vs. 29 ± 9 mm Hg, respectively; p<0.05) indicating a sympathetic activation in women with PIH. Power spectral analysis of heart rate variability did not show any significant difference between normotensive women and women who developed PIH. No difference in URI was found between subjects developing hypertension and normotensive women. Logistic regression analysis showed that all variables correctly predicted 88.9% normotensive women and 83.3% women who developed hypertension. Overall prediction was 86.7%. The most relevant parameter for predicting the development of PIH was diastolic MESOR. Cardiovascular tests improved the prediction of PIH. The study shows that ABPM could have a role in the screening of pregnant women at risk of developing hypertension.

Thirty-six growth-retarded fetuses selected from a population of 214 cases were studied by Doppler ultrasonography at weekly intervals for at least 4 weeks between the diagnosis of Doppler abnormalities suggestive of the existence of the brain-sparing effect (ie, ratio between umbilical artery and middle cerebral artery pulsatility indexes [Pis] above the 95th percentile of our reference limits) to the onset of antepartum late fetal heart rate (FHR) decelerations. Recordings were made from the umbilical artery, descending aorta, renal artery, internal carotid artery, and middle cerebral artery and the Pis were calculated. Statistically significant changes in PI occurred in all the vessels studied. However, different trends were found when the modifications in cerebral vessels were compared with those in fetal peripheral vascular beds and in the umbilical artery. In cerebral arteries, a nadir of vasodilatation was reached 2 weeks before the onset of antepartum late FHR decelerations, whereas significant changes in the peripheral and umbilical vessels occurred close to the onset of abnormal FHR patterns. This study demonstrates that despite a brain-sparing effect, there are further Doppler-detectable modifications in fetal circulation that differ between the cerebral and peripheral vascular beds. (Obstet Gynecol 1992;79:605-10)

TAX and IFO are active drugs in antracycline and cisplatin (Pt) resistant breast and ovarian cancer. The objective of this study was to assess the MTD of IFO given in a 3-day c.i. preceded by a fixed dose of TAX (175mg/m2) in a day hospital setting. Thirteen women with ovarian (9) and breast (4) cancer with advanced disease, pretreated with two or more chemotherapy regimens entered this study. Median age was 57 (range 33–69). All pts had previously received epidoxorubicin at a median dose of 360mg/m2(range 360–1260) alone or in combination with Pt or 5-fluorouracil and cyclophosphamide. All pts received a 3-hour infusion of a fixed dose of TAX through a central venous infuse port, followed by a 3-day c.i. of escalating doses of IFO (4-5-6-7 g/m2) and equal doses of Mesna, every 21 days in subsequent groups of pts. G-CSF was given only for G4 neutropenia (N) lasting longer than 72h or febrile G4 N. MTD was defined as follows: any G4 N lasting longer than 7 days or neutrophyls <100/mL for more than 72h despite G-CSF, any G4 febrile N for more than 72 h, any G4 thrombocytopenia, any G3 non-hematologic toxicity, except for alopecia. Hematologic toxicity and related events were:IFO dose level (g/m2)456no. of pts/no. of courses6/326/172/2median courses/pts (range)5.5 (1–8)2 (1–5)1leukopenia WHO G3/4 (% of courses)16 (50)7 (411)neneutropenia WHO G3/4 (% of courses)16 (50)11 (65)neanemia WHO G3 (% of courses)1 (3)4 (24)nefever 38°C (% of courses)1 (3)3 (18)neG-CSF vials/pts (% of courses)14 (10)35 (35)nered cells transfusion (% of courses)0 (0)4 (24)neNo other non-hematologic toxicity except alopecia was seen.Responses are as follows: 2 CR, 1 PR, 1 SO, 1 PO, 1 NE, among the pts treated at the first dose level; ISO and 5 too early, at the second dose level. The MTD has not yet been reached, but the combination TAX + IFO has acceptable toxicity and activity.

There is a direct relationship between the dose of IFO and EPI and the clinical response achievable in STS. We have, therefore, associated full doses of EPI (60mg/m2× 2 d, 1hr inf.) to increasing c.i. IFO + MESNA and G-CSF (300 μg/d, +7 to +14) in order to evaluate the maximum tolerated dose (MTD) of this program and obtain information on the clinical activity. The IFO starting dose level was 9g/m2(72hrs c.i.); further planned levels are 10.5g/m2(84 hrs) and 12g/m2(96 hrs). Eval for the definition of the MTD are those pts completing 3 consecutive cycles or developing a DLT. A DLT corresponded to: a G4 leucopenia or thrombocytopenia ≥ 5 day; any G3 neuro-nefrotoxicity; any other G4 toxicity. In case of I dose limiting toxicity (DLT) observed in the first 10 evaluable (eval) pts, the level is considered safe and closed; in case of 2 DLT the accrual of pts is pursued up to 15 eval pts. The MTD is defined as the level in which 3 pts/15 eval develop a DLT (20%). Since 09/93,28 pts with advanced previously untreated STS have been entered in the first 2 levels. Patients characteristics are: 14 males, 14 females, median age 49 (19–66), median PS (0–2); site of origin was extraskeletal in 20, visceral in 8. Measurable/evaluable parameters were present in 25 pts. Overall, 13 pts entered the tirst level: I early PRO, 2 not eval and 10 eval for the MTD definition (JOLT); 15 entered the second level: 2 early PRO, 2 not oval, 4 in progress and 7 eval for the MTD definItion (2DLT). The study is ongoing in order to complete the second level (15 eval pts).

We have started a phase I study in ABC and AOC pts to determine the maximum tolerated dose (MTD) of P to be given with E. Up to now, 21 pts (10 MBC and II AOC) have been accrued. Patient characteristics: median age 59 y (36–71); median PS (ECOG) 0 (0–1); all MBC pts had received adjuvant chemotherapy and all AOC pts were pretreated with cisplatin regimens; 18 pts were pretreated with a cumulative E dose of 360mg/sqm. P was given i.v. by a 3 hrs c.i. at 135mg/sqm (9 pts); 155mg/sqm (6 pts); 175mg/sqm (5 pts) and 200mg/sqm (1 pt). E was given at a fixed dose of 90mg/sqm i.v. bolus. Courses were repeated every 21 days. All the pts have been submitted to a clinical and instrumental cardiological monitoring including: physical examination, EKG, EKG Holter, late potentials, transoesofageal electrophysiologic study, cardiac echo-doppler. 81 courses have been administered: 46 at level 1, 26 at level 2, 12 at level 3 and 1 at level 4. The main side effects was: G4 neutropenia in 57% of the courses lasting a median of 4 days (1–6). No cardiac toxicity has been observed; the median left ejection fraction was 59% at study entry and 54% after 7 courses (total cumulative dose of E=990mg/mq). Response rate was 62.5% in ABC and 44.4% in AOC. PE is an active regimen; the main toxicity is short-lasting neutropenia and the MTD has not yet been reached. The study is ongoing.

Endometrium is unique since it is the only tissue that undergoes regular cyclic bleedings. Menstrual shedding is associated with the breakdown of endometrium, including the fragmentation of endometrial glands. To gain insight into the underlying basis of fragmentation of the endometrial epithelium during the menstrual phase, we examined the expression of proteins implicated in epithelial cell—cell binding in human endometria throughout the entire menstrual cycle. Western blotting failed to reveal differences in the relative amount of E-cadherin, α- or β-catenin or actin in the menstrual endometria compared with those in the proliferative or secretory phases. However, specific changes in the expression pattern of these proteins as well as desmoplakin I/II were detected by immunohistochemical staining in epithelial cells of menstrual endometria. Desmoplakin I/II, E-cadherin, α- and β-catenins and β-actin were localized to intercellular borders as well as the luminal and basal regions of glandular epithelium during the proliferative and secretory phases. Immunoreactivity of E-cadherin and α-catenin was confined to epithelial cells, whereas β-catenin and β-actin were present in epithelial cells, as well as in stroma and endothelial cells. Binding of F-actin to fluorescein isothiocyanate-labelled phalloidin localized this form of actin to the intercellular borders, and the basal and luminal cytoplasm of epithelial cells in proliferative and secretory endometria. Menstrual shedding was associated with disorganization of the site-specific distribution of desmoplakin I/II, E-cadherin and α- and β-catenins. This included focal patchy expression of these proteins or their total loss from cell—cell binding sites, as well as loss of F-actin in epithelial cells of menstrual endometrial glands. However, these changes were not observed in the basalis region that is not shed during the menstrual phase. These findings suggest that fragmentation of the endometrial glands during the menstrual phase is related to the disorganization and/or loss of the proteins at the adherens and desmosomal junctions, as well as loss of F-actin.

Background: Increased response rates in studies of patients with colon cancer have indicated that the cytotoxic effects of fluorouracil (5-FU) are potentiated by leucovorin (LV) and by methotrexate (MTX). However, preliminary studies using a sequential combination of MTX, LV, and 5-FU showed no additional potentiation. Purpose: We hypothesized that the lack of additional cell kill with this combination could be due to competition of LV with MTX for cellular uptake and reduced folate polygluta-mylation. We have tested this possibility by comparing the cytotoxicity of drug combinations containing MTX with that of drug combinations containing trimetrexate (TMTX), an anti-folate that does not compete with LV for uptake or polyglutamylation. Methods: Human lymphocytic leukemia CCRF-CEM cells were exposed to MTX or TMTX for 24 hours and to 5-FU during the last 4 hours of antifo-late exposure. LV was administered 30 minutes before 5-FU. Results: After 20 hours of exposure to TMTX or MTX, intracellular levels of phosphoribosyl pyrophosphate were elevated to a similar degree, and these levels did not decrease after a 30-minute exposure to LV. No additional cell kill was observed when LV was added to the MTX/5-FU combination, but cytotoxicity was enhanced when LV was added to the TMTX/5-FU combination. Conclusions: This study supports the hypothesis that the lack of additional cell kill when high-dose LV is added to the MTX/5-FU combination may be due to competition of MTX with LV for cellular uptake and/or competition of MTX or its polygluta-mates with polyglutamylation of reduced folates. Inasmuch as TMTX does not compete with LV and reduced folates for uptake and polyglutamylation, the synergy obtained with the combination of TMTX plus 5-FU and high-dose LV further supports this hypothesis. [J Natl Cancer Inst 84:1033–1038, 1992]

Apoptosis in human endometrial epithelium progressively increases from early to late secretory/menstrual phases and remains consistently more prominent in the basalis. It has been suggested that tumour necrosis factor (TNF) α secreted during the secretory/menstrual phases plays a role in induction of programmed cell death in these cells. In the present study, we characterized expression of receptors of TNFα, Fas antigen and BCL-2 in endometrial cells to gain insight as to whether this type of cell death in endometrium may be related to differential or preferential expression of these proteins at specific phases of the menstrual cycle. In addition, to relate production of TNFa to the development of apoptosis, the amount of TNFα released by human endometrium was measured. Immunostaining demonstrated that the TNF receptor (TNFr; p55/60)-I, TNFr-II (p75/80) as well as Fas protein were expressed in endometrial epithelium throughout the entire menstrual cycle. This expression was progressively diminished from the basalis towards the upper functionalis. In the proliferative phase, the expression of BCL-2 was prominent in the endometrial glands particularly in those residing in the basalis. This expression became weak as early as the third post-ovulatory day and remained low during the remaining phases of the menstrual cycle. The amount of TNFα released by endometrial fragments obtained from various phases of the menstrual cycle was determined. The amount of TNFα released into the culture medium by the endometrium was low in the proliferative phase. However, the amount of released TNFα progressively increased in the secretory phase and peaked in the menstrual phase. TNFr-I, TNFr-II, Fas, BCL-2 and TNFα could be identified by Western blot analysis of proteins extracted from endometrium. Therefore, endometrial epithelium by virtue of expression of receptors of TNFα as well as Fas protein is properly poised to respond to ligand signals that regulate apoptosis. Induction of apoptosis in endometrial epithelium and menstrual shedding may be related to loss of the protective effect of BCL-2 as well as to the amount of TNFα.