The impact of olaparib dose reduction and treatment interruption on treatment outcome in the SOLO2/ENGOT-ov21 platinum-sensitive recurrent ovarian cancer.

BACKGROUND: Maintenance treatment with poly (ADP-ribose) polymerase (PARP) inhibitor is now the standard of care in patients with BRCA-mutated platinum-sensitive recurrent ovarian cancer following response to chemotherapy. In the SOLO2 trial, adverse event (AE)-associated olaparib interruption, dose reduction, and discontinuation occurred in 50%, 28%, and 17% of patients, respectively. We used data from the SOLO2 trial to evaluate the impact of dose alterations on survival outcomes and identified baseline characteristics associated with dose alteration. PATIENTS AND METHODS: We computed relative dose intensity (RDI) defined as the received dose as a percentage of the standard dose (300 mg twice a day) during the first 12 weeks on treatment. Patients were categorized into RDI >98%, RDI 90%-98%, and RDI <90%. The association between RDI categories with progression-free survival (PFS) and overall survival (OS) were examined using a 12-week landmark Cox regression analysis. Logistic regression analysis was used to correlate baseline factors with RDI at 12 weeks. RESULTS: In patients on olaparib included in the landmark analysis (n = 185), the mean 12-week RDI was 91.4%. There was no significant difference across 12-week RDI >98% (n = 110), 90%-98% (n = 29), and <90% (n = 45) categories for PFS (median, 14.2 versus 19.3 versus 34.4 months; P = 0.37) and OS (median, 49.7 versus 49.5 versus 54.1 months; P = 0.84). Risk of RDI ≤90% increased with baseline performance status 1 [odds ratio (OR): 2.54; 95% confidence interval (CI): 1.11-5.82] any nausea (OR: 3.17; 95% CI: 0.9-11.23), and with body weight ≤70 kg (OR: 1.86; 95% CI: 0.92-3.76). CONCLUSIONS: Dose reduction and interruption for the management of olaparib-associated AEs during the first 12 weeks did not impact on PFS and OS. When counselling patients requiring dose reductions or interruptions due to AEs, the results of this study will help assure patients that their outcomes will not be adversely affected.

Exposure of fallopian tube epithelium to follicular fluid mimics carcinogenic changes in precursor lesions of serous papillary carcinoma.

OBJECTIVES: Ovulation-related inflammation is suspected to have a causal role in ovarian carcinogenesis, but there are no human models to study the molecular pathways. Our aim is to develop such an ex-vivo model based on human fallopian tube (FT) epithelium exposed to human follicular fluid (FF). METHODS: FT epithelium was dissociated from normal surgical specimens. FF was obtained from donors undergoing in-vitro fertilization. The cells were cultured on collagen-coated Transwells and incubated with FF for various periods of time. The transcriptomic changes resulting from FF treatment were profiled using Affymetrix expression arrays. Specific characteristics of the FT pre-cancerous lesions were studied using immunohistochemistry, immunofluorescence, RT-PCR and XTT assay. RESULTS: We show that FF exposure causes up-regulation of inflammatory and DNA repair pathways. Double stranded DNA breaks are induced. There is a minor increase in cell proliferation. TP53, which is the hallmark of the precursor lesion in-vivo, is accumulated. Levels of expression and secretion of Interleukin-8 are significantly increased. CONCLUSIONS: Our model addresses the main non-genetic risk factor for ovarian cancer, namely the impact of ovulation. This study demonstrates the biological implications of in-vitro exposure of human FT epithelial cells to FF. The model replicates elements characterizing the precursor lesions of ovarian cancer, and warrants further investigation of the linkage between repeated exposure to ovulation-related damage and accumulation of neoplastic changes.

Bowel obstruction in recurrent gynecologic malignancies: defining who will benefit from surgical intervention.

AIM: To define factors that could help select, in a cohort of gynecologic cancer patients with malignant gastro-intestinal obstruction, those most likely to benefit from palliative surgery. METHODS: In this retrospective study of patients with malignant gastro-intestinal obstruction who underwent palliative surgery in our institute over 7 years, outcome measures were oral intake, chemotherapy, and 30-day, 60-day and overall survival. Based on Cox proportional-hazards regression models and Kaplan-Meier curves with log-rank tests, a prognostic score was developed to identify those most likely to benefit from surgery. RESULTS: Sixty-eight palliative surgeries were performed in 62 patients with ovarian (69.1%), primary-peritoneal (8.8%), cervical (11.8%) or uterine (10.3%) malignancies. Procedures were colostomy (26.5%), ileostomy (39.7%), colonic stent (1.5%), gastrostomy (7.3%), gastroenterostomy (5.9%) and bypass/resection and anastomosis (19.1%). Eighteen patients died prior to discharge, within 3-81 days (median 25 days). The 30-day and 60-day mortality rates were 14.7% and 29.4%, respectively. Postoperative oral-intake and chemotherapy rates were 65% and 53%, respectively, with albumin level identified on multivariate analysis as the only significant predictor of both. Median postoperative survival was 106 days (3-1342). Bypass/resection and anastomosis was associated with improved survival. Ascites below 2 L, younger age, ovarian primary tumor, and higher blood albumin correlated with longer postoperative survival. A prognostic index based on these factors was found to identify patients with increased 30-day and 60-day mortality. CONCLUSIONS: Our proposed prognostic index, based on age, primary tumor, albumin and ascites, might help select those gynecological cancer patients most likely to benefit from palliative surgery.

Fetal gender assignment by first-trimester ultrasound.

OBJECTIVE: Ultrasound determination of fetal sex can benefit decision-making regarding invasive prenatal testing in pregnancies at risk of sex-linked genetic abnormalities. The aim of this study was to assess the accuracy of fetal sex determination by ultrasound at 12-14 weeks of gestation in a large cohort. METHODS: Fetal gender assessment by transabdominal ultrasound was performed in 656 singleton pregnancies at 12-14 weeks of gestation. The genital region was examined in the mid-sagittal plane. The angle of the genital tubercle to a horizontal line through the lumbosacral skin surface was measured. The fetus was assigned male gender if the angle was > 30 degrees , and female gender if the genital tubercle was parallel or convergent (<10 degrees ) to the horizontal line. At an intermediate angle of 10-30 degrees the gender was not determined. Crown-rump length (CRL) was measured in all cases. RESULTS: Gender assignment was possible in 613 of the 656 (93%) fetuses. Gender identification according to CRL was feasible in 85%, 96% and 97% of the fetuses at gestational ages of 12 to 12 + 3, 12 + 4 to 12 + 6 and 13 to 13 + 6 weeks, respectively. Phenotypic sex was confirmed in 555 newborns. The accuracy of male gender assignment in this group was 99-100% at all ages, and that of female gender assignment was 91.5% at 12 to 12 + 3 weeks, 99% at 12 + 4 to 12 + 6 weeks and 100% at 13 to 13 + 6 weeks. CONCLUSION: Prenatal gender assignment by ultrasound has a high accuracy rate at 12-14 weeks. These results indicate that invasive testing can probably be carried out in fetuses identified as males at this gestational age. However, in fetuses identified as female at a CRL of <62.6 mm, despite the relatively high 91.5% accuracy rate, the decision regarding invasive testing should be postponed until a higher CRL is achieved.

Abnormalities of somatic peptide-containing nerves supplying the pelvic floor of women with genitourinary prolapse and stress urinary incontinence.

OBJECTIVES: To test the hypothesis that genital prolapse may be related to peripheral nerve abnormalities, we examined the changes occurring to peptide-containing nerve processes supplying the periurethral muscles in women with stress urinary incontinence associated with prolapse. METHODS: Thirty patients with genital prolapse and 10 age-matched control subjects entered the study. All patients were evaluated by urodynamic investigations. Ten of 30 patients had pure stress urinary incontinence; none of the control subjects was incontinent. During surgery, four biopsy samples were obtained from each woman from the periurethral and perirectal muscles. The muscle sections were processed for immunohistochemistry using specific antibodies to glial (S-100 protein) and general neuronal markers (neuron-specific enolase) and neuropeptides, including neuropeptide Y, vasoactive intestinal polypeptide, and substance P. The evaluation of immunolabeled nerves was based on a semiquantitative analysis that allowed for a four-point ordinate scale score. RESULTS: S-100 and neuron-specific enolase immunoreactive nerve fibers, running either singly or in small bundles, along with a dense network of neural processes containing neuropeptide Y, vasoactive intestinal polypeptide, and substance P, were found throughout the connective tissue and striated muscle of the control specimens. In contrast, in the muscle specimens from those with genitourinary prolapse, both the density and the intensity of neuropeptide Y, vasoactive intestinal polypeptide, and substance P immunoreactive nerves were markedly reduced compared with the control specimens. CONCLUSIONS: The evidence of a reduced peptide-containing nerve supply to the perineal muscles provides a morphologic basis suggesting that neural abnormalities contribute to the pathogenesis of genital prolapse and urinary incontinence.

Strict glycemic control in diabetic pregnancy-implications for second-trimester screening for Down syndrome.

OBJECTIVES: Studies in the early 1990s showed that the normal levels of the biochemical markers used to screen for Down syndrome in the second trimester of pregnancy differ between healthy women and women with insulin-dependent diabetes mellitus (IDDM). Thereafter, most laboratories adopted correcting factors to adjust for these differences. However, the current validity of these factors in light of the recent improvements in glycemic control in diabetic pregnancy has not been investigated. METHODS: The sample consisted of 35 pregnant women with strictly controlled IDDM and 40 healthy controls matched for age and gestational week. All women had singleton pregnancies and were followed till delivery. RESULTS: Comparison of the triple test results between the two groups after adjustment with the traditional corrective factors yielded no significant differences in serum levels of any of the markers (unconjugated estriol, human chorionic gonadotrophin, alpha-fetoprotein). CONCLUSIONS: These results suggest that the recent improvement in glycemic control of pregnant women with IDDM changes the metabolic milieu that might cause the biochemical differences with healthy pregnant patients.

Elastin-based biopolymers: chemical synthesis and structural characterization of linear and cross-linked poly(OrnGlyGlyOrnGly).

Poly(OrnGlyGlyOrnGly) was synthesized by classical procedures in solution. The monomeric sequence -OrnGlyGlyOrnGly- was chosen as a modification of -ValGlyGlyValGly-, typical of elastin, to impart primary amine functionality, susceptible to cross-linking with appropriate bifunctional reagents. Herein we focus on the cross-linking of poly(OrnGlyGlyOrnGly) with glutaraldehyde. The polymers, both linear and cross-linked, were characterized and investigated for their molecular and supramolecular properties. Circular dichroism studies performed on linear poly(OrnGlyGlyOrnGly) revealed a variety of conformations similar to elastin. At a supramolecular level, different kinds of aggregates were found such as the elastin-like twisted-rope pattern of filaments and fibrils, together with other specific morphologies, similar to those recently identified in some elastin-mimetic polypeptides.

Effect of P-glycoprotein expression on outcome in the Ewing family of tumors.

This study was designed to determine the prognostic significance of multidrug resistance, mediated by P-glycoprotein (Pgp) expression, in Ewing sarcoma. The clinical and laboratory features, treatment protocol, and outcome of 75 patients with Ewing sarcoma or peripheral neuroectodermal tumor treated between 1972 and 1997 were reviewed. Pgp expression was tested with the monoclonal antibody JSB-1. Thirty-four (64%) of the 53 tissue samples from untreated patients stained positive for Pgp. Progression-free and overall survival were 44 and 59%, respectively, in patients with negative findings, and 28 and 41% in those with positive findings; neither difference was significant. Of the 12 relapsed patients, 6 (50%) expressed more Pgp after chemotherapy than at diagnosis and 4 (33%) expressed less. Within these subgroups, 5 out of 6 and 3 out of 4 died from the disease. No correlation was found between Pgp and known prognostic factors of Ewing tumors. Pgp expression is probably an intrinsic factor of Ewing tumors but has no correlation to prognosis.

Are singleton assisted reproductive technology pregnancies at risk of prematurity?

PURPOSE: Our purpose was to determine the risk of premature delivery among singleton pregnancies derived from assisted reproduction technology (ART). METHODS: Ninety-five singleton ART pregnancies and 190 matched spontaneous pregnancies were assessed for preterm delivery rates, pregnancy complications, and cesarean section rates in a retrospective study at an academic medical center. RESULTS: Among the ART singleton deliveries group (n = 95), 19 (20%) were preterm, which was statistically significantly higher than the 4% (8 of 190) found in the control group. Among the pregnancies achieved by intracytoplasmic sperm injection (ICSI) in the severe male-factor infertility subgroup (n = 22), only one preterm delivery occurred (4.5%). CONCLUSIONS: Singleton ART pregnancies are at an increased risk of preterm delivery compared to singleton pregnancies after spontaneous conception. The higher rate may be attributed to various infertility cofactors, such as uterine malformations, previous operative procedures that involved cervical dilatation, and a history of pelvic infection. This is supported by the finding that ICSI-derived pregnancies in couples with strict male-factor infertility are not at an increased risk of preterm delivery.

Influence of hormone replacement therapy on postmenopausal pelvic organs.

OBJECTIVE: To assess the influence of hormone replacement therapy (HRT) on the pelvic organs of postmenopausal women by vaginal ultrasonography. DESIGN: The study (case-control) included 753 consecutive, postmenopausal women who were referred for routine transvaginal ultrasound examination. A total of 290 women who were using HRT at the time of examination (study group) were compared with 463 who were not treated (control group). RESULTS: The women using HRT were younger and had been menopausal for a shorter period, compared with those who had not been treated. Mean uterine volume, endometrial thickness and ovarian area were all increased in the HRT group, compared to the control group. A negative correlation was found between menopausal age and uterine volume, and ovarian area in both treated and untreated groups. However, endometrial thickness was negatively correlated with menopausal age in the untreated group only. After controlling for various parameters, a multivariate logistic analysis demonstrated that endometrial thickness was treatment status-dependent only. Uterine volume was also treatment status-dependent, but was also negatively correlated with menopausal age. As expected, the endometrium was thicker and the uterine volume was larger in the treated group. Ovarian area was not found to be treatment-dependent for all menopausal ages. CONCLUSIONS: Postmenopausal women treated with HRT have a larger uterus and thicker endometrium than those of non-treated matched controls. There is a negative correlation between menopausal age and uterine and ovarian size. Endometrial thickness was found to be negatively correlated with menopausal age in only the untreated group, and is almost entirely HRT-dependent. In contrast to the uterus and the endometrium, the ovaries are not influenced by HRT.

Effects of alprostadil on blood rheology and nucleoside metabolism in patients affected with lower limb chronic ischaemia.

The acute (0.57 microg/kg i.v. in 2 hours) and long-term (0.57 microg/kg i.v. in 2 hours for 5 days over 4 weeks) effects of the PGE1 analogue alprostadil were studied in patients affected with intermittent claudication. Whole Blood Viscosity (WBV), Whole Blood Filterability (WBF), haematocrit (Htc) and fibrinogen plasma concentration, were studied together with P50, 2,3-diphosphoglycerate, and adenosine plasma levels. Moreover, in the long-term study, pain-free (PFWD) and maximal walking distance (MWD) were measured. Single alprostadil infusion induced an improvement in WBV, WBF, and oxygen transport, and an increase in adenosine plasma levels. Long-term alprostadil administration produced a decrease in WBV only, without significant changes in WBF, Htc, fibrinogen, P50, 2,3-diphosphoglycerate, also inducing a significant prolongation of PFWD and MWD. The possibility is suggested that pulse rises in adenosine plasma levels play a role in the effects of chronic alprostadil administration, maybe in a way similar to that observed in the phenomenon of ischaemic preconditioning,

Spectrum of normal intrauterine cavity sonographic findings after first-trimester abortion.

OBJECTIVE: To characterize the sonographic appearance of the uterine cavity after uncomplicated first-trimester abortion. METHODS: Women who underwent uterine evacuation for first-trimester abortion were referred for endovaginal sonographic examination within the week after the procedure. Special attention was directed to characterizing the intrauterine cavity. Demographic and clinical parameters were collected. A repeated postmenstrual examination was carried out in selected cases. RESULTS: In all, 57, 10, and 7 sonographic examinations were performed after termination of pregnancy, incomplete (spontaneous) abortion, and missed abortion, respectively. Fifty-seven (77%) of the 74 examinations showed considerable amounts of intrauterine content with various echogenicities (anteroposterior thickness range, 7-61 mm). No association could be documented between the pattern of appearance and gravidity, parity, gestational age, or type of abortion procedure. All postmenstrual reevaluations of patients with excessive amounts of intrauterine material at the initial examination (n = 7) showed empty intrauterine cavities. CONCLUSION: Within the week after first-trimester abortion, the uterine cavity is seldom empty. Thick heterogeneous material is an expected finding after examination. By being familiar with this normal range of appearances, clinicians can avoid unnecessary repeated invasive evacuation procedures. A follow-up sonographic evaluation during the follicular phase of the next menstrual cycle is recommended to confirm the absence of retained products of pregnancy.

Early sonographic detection of a 'human tail': a case report.

We report on a newborn in whom an echogenic protrusion arising in the caudal region was detected at 12 weeks' gestation. Subsequent ultrasound examinations at weeks 15 and 22 failed to demonstrate this finding. After birth, the infant was found to have a pilonidal sinus. The pilonidal sinus may represent a remnant of the embryonic appendage ('human tail') that usually disappears by the end of the 8th week of gestation. This case might support the theory of congenital pilonidal sinus origin.

Outcome of pregnancies derived from assisted reproductive technologies: IVF versus ICSI.

PURPOSE: To compare the course and outcome of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) pregnancies. METHODS: A retrospective study was conducted in a university-affiliated IVF unit with 200 patients who conceived in 1996-1997, 100 with ICSI and 100 with IVF. Data were retrieved from our prospectively created computerized database. In addition, all patients were interviewed by telephone, and the interviewing physician completed a detailed questionnaire. Findings for the IVF and ICSI pregnancies were compared. The main outcome measures were maternal age, implantation rate, early pregnancy complications, clinical abortion rate, multiple pregnancy delivery rate, gestational age at delivery, mode of delivery, and birth weight. RESULTS: In all, 238 children were born, including 104 singleton infants (45 IVF, 59 ICSI), 49 twin pairs (28 IVF, 21 ICSI), and 12 triplet sets (3 IVF, 9 ICSI). Statistically significant differences between the ICSI and IVF groups were noted for maternal age (31.3 +/- 4.4 vs. 33.4 +/- 4.8, respectively, P < 0.005) and clinical abortion rate (11% vs. 24%, respectively, P < 0.05). CONCLUSIONS: ICSI pregnancies in our series were characterized by a lower clinical abortion rate than IVF pregnancies, probably because of the mean younger age of the ICSI group.

Tc-99m MIBI to evaluate children with Ewing's sarcoma.

PURPOSE: Tc-99m MIBI has been used increasingly to evaluate benign and malignant tumors because of its tumor-seeking properties and ability to provide an imaging assessment of multiple-drug resistance. This study investigated the clinical utility of Tc-99m MIBI in the management of Ewing's sarcoma in children. METHODS: Thirteen Tc-99m MIBI studies in nine (six male, three female) patients ages 6.5 to 20 years (mean, 13.4 years) with Ewing's sarcoma were reviewed. All patients had imaging studies at diagnosis, and four had follow-up studies during or after therapy. Scintigraphy was evaluated for Tc-99m MIBI uptake within the tumor and in metastases, which other imaging modalities had shown to be present in four patients. Scintigraphic results were correlated with the clinical course in all patients and with tumor P-glycoprotein status in six patients. RESULTS: Tc-99m MIBI accumulated in 6 of 9 primary tumors and did not accumulate in one recurrent tumor. No metastases showed Tc-99m MIBI uptake. The presence or absence of Tc-99m MIBI uptake at diagnosis or after therapy carried no prognostic significance. Tc-99m MIBI was present in the two tumors that were P-glycoprotein positive and in only one of four tumors that were P-glycoprotein negative. CONCLUSION: Tc-99m MIBI imaging does not appear to be useful in Ewing's sarcoma.

Increase in plasma adenosine during brain ischemia in man: a study during transient ischemic attacks, and stroke.

Adenosine is a "retaliatory metabolite" which accumulates during experimental brain ischemia and has vasodilatory and putative neuroprotective effects. The aim of this study was to assess whether human cerebral ischemia and necrosis-evaluated in the clinical models of transient ischemic attack (TIA) and stroke, respectively-acutely raise plasma adenosine levels. We studied 20 patients: 10 with TIA and 10 with stroke. In all, blood was serially sampled for assessment of plasma adenosine by an high-performance liquid chromatography method. Sampling occurred on peripheral blood during TIA and stroke upon admission, and serially thereafter every day up to 7 days and every other day up to 20 days. We found that in TIA and stroke patients, peripheral adenosine levels were increased to a similar extent upon admission (TIA = 264 +/- 53 vs. stroke = 257 +/- 60 nM, p = ns), peaked on the day 2 for TIA (300 +/- 60) and on day 3 for stroke (289 +/- 43) patients, and steadily decreased towards the normal range, reached by all TIA patients by day 5 and by stroke patients by day 15. Stroke and TIA are associated with a rapid increase in circulating plasma adenosine concentration in man, detectable in peripheral vein. The adenosine surge likely mirrors an increased production from the ischemic brain, and it lasts days (for TIA) and weeks (for stroke) after the acute event.

Adenosine and chronic ischemia of the lower limbs.

Adenosine is an endogenous nucleoside with multiple biological properties which plays a central role in the pathophysiology of tissue ischemia. Adenosine signals an imbalance between oxygen demand and supply, and it initiates responses to redress such a discrepancy. Besides its vasodilating properties, adenosine possesses anti-platelet and anti-neutrophil activities and provides cytoprotection. Adenosine is presumably the main mediator of the preconditioning phenomenon. During ischemia of the lower limbs, adenosine plays a physiological role by inducing vasodilatation and by preventing microcirculatory failure. Exercise training prolongs claudication distance possibly by inducing pulse increases of adenosine and consequently skeletal muscle preconditioning. Moreover, the adenosine increase which follows the administration of some drugs, such as buflomedil and propionylcarnitine, opens new perspectives in the management of leg ischemia. In fact, the concept arises of an ischemic (exercise-dependent) or pharmacologic preconditioning in the treatment of patients with claudication.

The rationale for requesting a second consecutive sperm ejaculate for assisted reproductive technology.

We assessed the value of requesting a second semen sample provided within 1 hour of the first in cases of unacceptable ejaculate quality (compared to previous occasions) or very poor semen characteristics. The study population consisted of 109 males with severe oligo-terato-astenospermic (OTA) syndrome in an assisted reproduction program. Semen volume, sperm count and sperm motility were recorded in the first and second samples with a Makler Counting Chamber before sperm processing, and total motile sperm in the ejaculate was calculated. Differences in sperm parameters between the consecutive samples were determined by paired-sample t test. In 36 cases (33%) the second sample was found to be superior in quality to the first and was therefore used for the fertilization process. Of the 12/109 cases in which the first ejaculate demonstrated no motile sperm, five (41%) had detectable motile sperm in the second (total 0.1 x 10(6), 0.2 x 10(6), 0.3 x 10(6), 8.4 x 10(6) and 20.8 x 10(6)). We conclude that a request for second ejaculate immediately after the first in males with poor semen quality or no detectable motile sperm can yield a better sample in a significant percentage of cases. Using this method, clinicians can avoid the utilization of elaborate sperm processing techniques and the need for unnecessary micromanipulative fertilization.

Systemic adenosine increase during cold pressor test is dependent on sympathetic activation.

1. Following local vasoconstriction-inducing stimuli, such as the cold pressor test (CPT), significant changes occur in haemodynamics, with a rise in arterial blood pressure and heart rate (HR) due to the activation of the sympathetic nervous system. Among the compensatory mechanisms to local ischaemia, the endogenous nucleoside adenosine (ADO) has been suggested to play a relevant role by contributing to sympathetic stimulation. The possibility was investigated that CPT-induced increases in plasma ADO levels were not only an expression of the increased production of ADO in the ischaemic area, but also a consequence of systemic sympathoexcitatory mechanisms, thus showing a bidirectional involvement of the mechanisms of ADO formation. 2. The CPT was performed in 15 volunteers and mean arterial blood pressure (MABP) and HR were evaluated, together with plasma levels of noradrenaline (NA) and ADO in the tested and contralateral arm. The 15 subjects were then divided into three groups of five that were treated with either 5 mg transdermal clonidine weekly, 100 mg atenolol daily or 600 mg aminophylline twice daily. After 1 week treatment, the same test was repeated in the respective groups. 3. The CPT induced a rise in MABP and HR and an increase in plasma levels of NA and ADO. Increases in ADO were more pronounced in the tested arm. Clonidine blunted the haemodynamic response and NA release, while increases in ADO increase were reduced to a greater extent in the contralateral arm rather than the tested arm. Atenolol only affected MABP and HR without any effect on NA and ADO levels. Theophylline did not show any effect on CPT-induced changes. 4. In conclusion, local vasoconstriction and ischaemia induced in one arm following CPT are associated with haemodynamic changes dependent on the activation of the sympathetic system. The observed increase in plasma levels of ADO seems to be, in part, a direct expression of local responses to ischaemia (pre-dominant in the tested arm), but also appears as the consequence of systemic sympathoexcitatory mechanisms. Such increases in ADO are not dependent on a beta 1-adrenoceptor-mediated mechanism. Finally, theophylline, at a therapeutic dose, has no effect on the response to CPT.