Randomised controlled trial on the effect of clomiphene citrate and gonadotropin dose on ovarian response markers and IVF outcomes in poor responders.

STUDY QUESTION: Does the gonadotropin (GN) starting dose and the addition of clomiphene citrate (CC) during the early follicular phase influence oocyte yield in poor responders undergoing ovarian stimulation for IVF treatment? SUMMARY ANSWER: The number of retrieved oocytes was similar regardless of the starting dose of GN (150 versus 450 IU) with or without the addition of CC (100 mg from Day 3 to 7 versus placebo). WHAT IS KNOWN ALREADY: ART in poor responders is a challenge for patients and clinicians. So far, randomised controlled studies addressing interventions have shown that neither the GN dose nor the addition of oral medication has any significant effect on the clinical outcome of ART in poor responders. There is limited knowledge about the effect of GN starting dose in combination with CC during the early follicular phase of ovarian stimulation on ovarian response markers and ART outcome. STUDY DESIGN, SIZE, DURATION: This single-centre randomised double-blinded clinical trial was conducted from August 2013 until November 2017. Using the Bologna criteria, 220 of 2288 patients (9.6%) were identified as poor responders and 114 eligible participants underwent ovarian stimulation in a GnRH-antagonist protocol for ART. PARTICIPANTS/MATERIALS, SETTING, METHODS: The participants were equally randomised to one of four treatment arms: Group A (n = 28) received 100 mg CC (Day 3-7) and a starting dose of 450 IU HMG, Group B (n = 29) received 100 mg CC and a starting dose of 150 IU HMG, Group C (n = 30) received placebo and a starting dose of 450 IU HMG and Group D (n = 27) received placebo and a starting dose of 150 IU HMG. Serum levels of FSH, LH, estradiol and progesterone were measured on Day 1 and 5 and on the day of ovulation induction. Available embryos were cultured up to the blastocyst stage and were always transferred in the same cycle. The primary outcome was the number of oocytes collected after ovarian stimulation. Other outcome measures were response to ovarian stimulation, embryo development and obstetrical outcome. MAIN RESULTS AND THE ROLE OF CHANCE: All study participants (n = 114) fulfilled at least two of the Bologna criteria for poor responders. Median age of the study population was 38.5 years. There were 109 patients who underwent oocyte retrieval. The number of oocytes retrieved was similar among the groups (±SD; 95% confidence intervals); A: 2.85 (±0.48; 2.04-3.98), B: 4.32 (±0.59; 3.31-5.64); C: 3.33 (±0.52; 2.45-4.54); D: 3.22 (±0.51; 2.36-4.41); P overall = 0.246. However, ovarian stimulation with 150 IU plus CC resulted in a higher number of blastocysts compared to ovarian stimulation with 450 IU plus CC (±SD; 95% confidence intervals); A: 0.83 (±0.15; 0.58-1.2), B: 1.77 (±0.21; 1.42-2.22); P overall = 0.006. Mean FSH serum levels were lower in the groups with a starting dose of 150 IU. Adding CC did not affect mean serum FSH levels. There were no differences in estradiol concentrations among the groups. Endometrial thickness was lower in the groups receiving CC. The overall live birth rate (LBR) was 12.3%, and the cumulative LBR was 14.7%. LIMITATIONS, REASONS FOR CAUTION: The trial was powered to detect differences in neither the number of blastocysts nor the LBR, which would be the preferable primary outcome of interventional trials in ART. WIDER IMPLICATIONS OF THE FINDINGS: We found that ovarian stimulation with 150 IU gonadotrophin in combination with 100 mg CC produced more blastocysts. The effect of adding CC to GN on LBR in poor responders remains to be proven in randomised trials. High GN doses (450 IU) resulted in high FSH serum levels but increased neither the estradiol levels nor the number of retrieved oocytes, implying that granulosa cell function is not improved by high FSH serum levels. Lower starting doses of GN lead to a reduction of costs of medication. The small but significant difference in blastocyst formation and the lower FSH levels in the treatment groups receiving less GN may be an indication of better oocyte quality with higher developmental competence. STUDY FUNDING/COMPETING INTEREST(S): The costs for the HMG used for ovarian stimulation were provided by IBSA Switzerland. The study was also supported by the Repronatal Foundation, Basel, Switzerland. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: NCT01577472. TRIAL REGISTRATION DATE: 13 April 2012. DATE OF FIRST PATIENT'S ENROLMENT: August 2013.

Letrozole may be a valuable maintenance treatment in high-grade serous ovarian cancer patients.

OBJECTIVES: Endocrine therapy is used as maintenance in estrogen receptor (ER) positive breast cancers and has been proposed in low-grade serous ovarian cancers (LGSOC). Here we examine a rationale for its use as maintenance in high-grade serous ovarian cancers (HGSOC). METHODS: We accessed the TCGA PANCAN dataset to evaluate the expression of ESR1. ESR1 expression data on all cancers (n=8901) and HGSOC (n=527) were followed by investigation of ER expression via immunohistochemistry (IHC) (n=4071). The same was performed in an independent cohort for matched primary and recurrent HGSOC (n=80). Finally, newly diagnosed ER+ HGSOC patients were offered a maintenance therapy with Letrozole. RESULTS: ESR1 was strongly expressed in similar levels in HGSOC as in breast cancer. We found a strong ER expression via IHC in both the primary and matched recurrent HGSOC, particularly in the Platinum-resistant subgroup. The additional use of Letrozole as maintenance treatment was associated with a significantly prolonged recurrence free interval (after 24months 60% when taking Letrozole versus 38.5% in the control group; p=0.035; RFS: IC50 reached by one subject versus 13.2months). This effect was also present in patients treated additionally with Bevacizumab; 20.8% of patients had no recurrence after 12months compared to 87.5% when taking Letrozole in addition to Bevacizumab (p=0.026). CONCLUSIONS: Primary HGSOC have a slightly higher ESR1 than and a similar ER expression breast cancer where aromatase inhibitor maintenance is routine for decades. Here we demonstrate evidence for the usefulness of Letrozole in HGSOC, particularly in patients with chemotherapy resistance or residual disease.

Increased Prevalence of Flammer Syndrome in Patients with Retinitis Pigmentosa.

BACKGROUND: "Retinitis pigmentosa" refers to a group of degenerative eye diseases with a genetic background. Flammer syndrome encompasses a set of symptoms and signs, mainly but not exclusively related to dysregulation of blood vessels. The purpose of the present study was to determine, with the help of a questionnaire, whether symptoms of Flammer syndrome occur more often in patients with retinitis pigmentosa than in controls. METHODS: 76 patients with retinitis pigmentosa (members of the Swiss patient organization for retinitis pigmentosa) and 274 control subjects answered a questionnaire (Flammer Syndrome Questionnaire) on 15 symptoms and signs of Flammer syndrome. RESULTS: Seven of 15 symptoms and signs of Flammer syndrome were significantly more often positive in retinitis pigmentosa patients than in controls. Six additional symptoms and signs occurred non-significantly more often and 2 non-significantly less often in patients with retinitis pigmentosa. CONCLUSION: Retinitis pigmentosa patients suffer significantly more often from symptoms and signs of the Flammer syndrome than control subjects. This includes low body mass index, low blood pressure, feeling cold, migraine, increased smell perception and perfectionism. The reason for this association between retinitis pigmentosa and Flammer syndrome and the potential implications need to be determined.

Retinal venous pressure in the non-affected eye of patients with retinal vein occlusions.

BACKGROUND: To measure the retinal venous pressure (RVP) in both eyes of patients with unilateral central retinal vein occlusions and to compare these values to controls. METHODS: The study included 31 patients with unilateral central retinal vein occlusions (CRVO) and 31 controls who were matched by age, sex, and systemic disease. RVP was measured in all patients bilaterally by means of contact lens ophthalmodynamometry, and the RVP measurements of the affected and unaffected eyes of patients were compared to the RVPs of controls. Ophthalmodynamometry is done by applying an increasing pressure on the eye via a contact lens. The minimum force required to induce a venous pulsation is called ophthalmodynamometric force (ODF). The RVP is defined and calculated as the sum of ODF and intraocular pressure (IOP) [RVP = ODF + IOP]. RESULTS: The RVP group means ± SD were as follows: patient's affected eyes (45.0 ± 11.6 mmHg), patient's unaffected eyes (38.0 ± 11.1 mmHg) ,and (17.7 ± 6.7 mmHg) in the eyes of controls. The values of RVP, even in the patients unaffected eyes, were significantly higher than in the eyes of controls (P < 0.001). CONCLUSIONS: In patients with CRVO, the RVP is increased in both the affected as well as in the unaffected contralateral eye.

Frequency of symptoms and signs of primary vascular dysregulation in Swiss and Korean populations.

BACKGROUND: Primary vascular dysregulation syndrome (also called Flammer syndrome) is related to certain eye diseases, particularly normal tension glaucoma. Primary vascular dysregulation is characterized by a number of symptoms and signs (e.g., cold hands and/or feet, low blood pressure), that occur more frequently in subjects with primary vascular dysregulation compared to the general population. The aim of the present study was to test and compare the relative frequency of symptoms and signs related to primary vascular dysregulation in unselected populations in Switzerland and Korea. SUBJECTS AND METHODS: Swiss (n=259) and Korean (n=1116) subjects filled out our questionnaire containing 15 questions related to symptoms and signs of primary vascular dysregulation. RESULTS: In the populations studied, seven of 15 symptoms and signs of primary vascular dysregulation (increased smell perception, increased pain sensation, increased response to certain drugs, low body mass index, feeling cold, cold hands and/or feet, and headaches) occurred significantly more often in the Swiss population than in the Korean population, whereas five symptoms and signs (reversible skin blotches, tendency toward perfectionism, long sleep onset time, tinnitus, and dizziness) occurred significantly more often in the Korean population. CONCLUSION: The relative frequency of these symptoms and signs of primary vascular dysregulation in an unselected average population differs between Switzerland and Korea. Therefore, if a diagnosis of primary vascular dysregulation is based on the self-reported symptoms and signs of the patient, they must be compared with the frequency of symptoms and signs in the corresponding local population.

Is water delivery a good idea to prevent obstetric anal sphincter injuries in low risk primiparae? An exploratory study in a Swiss public teaching hospital.

OBJECTIVE: Obstetric anal sphincter injuries are feared perineal injuries that are associated with increased pelvic floor disorders. The knowledge of influencing factors as the mode of delivery is therefore important. The aim of this study is to compare the rate of obstetric anal sphincter injuries in primiparae after water and bed deliveries. STUDY DESIGN: In this retrospective cohort study 3907 primiparae gave birth in water or on a bed in a Swiss teaching hospital. The diagnosis of obstetric anal sphincter injuries was confirmed by a consultant of obstetrics and gynecology and treated by them. The rates of these injuries after water and bed births were compared. Subgroup analysis was performed to detect possible associative factors, such as birth weight, episiotomy, use of oxytocin in first and second stage of labor. RESULTS: 1844 (47.2 %) of the primiparae had a water delivery and 2063 (52.8 %) a bed delivery. 193 (4.94 %) were diagnosed with obstetric anal sphincter injuries, of which 68 (3.7 %) had a water delivery and 125 (6.1 %) a bed delivery, p < 0.001. Subgroup analysis revealed that, in the first and second stage of labor, the rate of obstetric anal sphincter injuries with oxytocin was significantly lower in water than in bed deliveries; p = 0.025, p < 0.017, respectively. The rate of obstetric anal sphincter injuries in the birth weight or episiotomy subgroups did not reach significance. CONCLUSIONS: In a teaching hospital setting with standardized labor management, primiparae with a water delivery have the lowest risk for obstetric anal sphincter injuries.

Detection of retinal glial cell activation in glaucoma by time domain optical coherence tomography.

BACKGROUND: Activated retinal astrocytes and Müller cells (ARAM) have been found in glaucoma patients. This study investigated whether presumed ARAM can be detected by optical coherence tomography (OCT), and assessed their relationship to the retinal nerve fiber layer (RNFL) thickness. PATIENTS AND METHODS: Single-center observational study involving 35 age-matched healthy controls and 19 patients with primary open-angle glaucoma (POAG) between 45 - 82 years of age. Presumed ARAM was defined as patchy, discrete glittering but transparent changes of the macula. The retina was documented by red-free photography to assess distribution of ARAM, and compared to the RNFL thickness measured around the fovea by OCT. A linear mixed effects model was used to detect a difference between eyes with ARAM versus eyes without ARAM. RESULTS: ARAM was not found in healthy subjects. The mean RNFL around the fovea was not significantly thicker in healthy controls (34.01 SD ± 22.24) than in POAG patients with ARAM (30.86 microns SD ± 15.09; p = 0.36) or without ARAM (33.19 microns SD ± 19.87; p = 0.46). Furthermore, the median RNFL thickness was similar to the control group (29 microns) but slightly thinner in POAG patients (each 27 microns with ARAM and without ARAM). In a subgroup analysis of POAG patients with ARAM, the within subject standard deviation of RNFL was significantly lower in areas with ARAM (SD 10.12) than in areas without ARAM (SD 17.30) (p < 0.001). CONCLUSIONS: Although the mean and median RNFL thickness was comparable between the groups, the variability of the RNFL thickness was significantly lower in areas with ARAM than in areas without ARAM suggesting that ARAM may mask RNFL loss in POAG patients.

Influence of alitretinoin on the pharmacokinetics of the oral contraceptive ethinyl estradiol/norgestimate.

BACKGROUND: Alitretinoin (9-cis retinoic acid) is currently registered in many European countries and in Canada as the only licensed treatment for severe chronic hand eczema unresponsive to potent topical corticosteroids. Alitretinoin, like all retinoids, is teratogenic, and women of child-bearing potential must strictly adhere to pregnancy-prevention measures. AIM: To investigate the influence of alitretinoin on the pharmacokinetics (PK) of ethinyl estradiol/norgestimate (Ortho Tri-Cyclen 28(®)), a commonly prescribed combination oral contraceptive. METHODS: In total, 16 healthy premenopausal women received three consecutive cycles of the triphasic contraceptive ethinyl estradiol/norgestimate together with concomitant oral alitretinoin 40 mg once daily during cycle 2. Steady-state PK (noncompartmental analysis) of ethinyl estradiol, 17-deacetyl norgestimate, alitretinoin and its main metabolite 4-oxo-alitretinoin were assessed alone and in combination. RESULTS: The PK profiles of ethinyl estradiol and 17-deacetyl norgestimate were similar when contraceptives were given alone or with alitretinoin, and the area under the plasma concentration vs. time curve and the maximum concentration met the conventional criteria for PK equivalence. Similarly, the influence of ethinyl estradiol/norgestimate on systemic exposure to alitretinoin and 4-oxo-alitretinoin was not clinically relevant. Alitretinoin was well tolerated when given either alone or with ethinyl estradiol/norgestimate. CONCLUSIONS: There was no clinically relevant influence of alitretinoin on the PK of ethinyl estradiol/norgestimate, and no influence of ethinyl estradiol/norgestimate on systemic exposure to alitretinoin and 4-oxo-alitretinoin. Consequently, oral contraception with ethinyl estradiol/norgestimate is an appropriate primary method of birth control during alitretinoin treatment for women of childbearing potential.

Pharmacokinetic interactions between alitretinoin and ketoconazole or simvastatin or ciclosporin A.

BACKGROUND: Based on in vitro data with isolated cytochrome P450 (CYP) isoenzymes, alitretinoin interacts only with CYP3A4, and the potential for drug-drug interactions is considered negligible. AIM: To confirm in humans the lack of potential interactions between CYP3A4 and alitretinoin in vivo. METHODS: This was a multiple-dose, open-label, parallel-group, single-centre study, which enrolled 54 healthy male volunteers aged 18-45 years. Subjects were divided into three groups, with 18 in each group: group 1 received either alitretinoin 30 mg and ketoconazole 200 mg, group 2 alitretinoin 30 mg and simvastatin 40 mg, and group 3 alitretinoin 30 mg and ciclosporin A 300-mg. RESULTS: At the highest therapeutic dose of 30 mg, alitretinoin had no significant effect on the pharmacokinetics (PK) of ketoconazole and ciclosporin A. There was a significant but not clinically relevant effect of simvastatin on the area under the curve (AUC) of plasma concentration vs. time and on maximum plasma concentration (C(max)) after repeated administration of alitretinoin. Exposure to simvastatin concomitantly with alitretinoin was decreased by 16% for AUC and 23% for C(max). The CYP3A4 ± PgP substrates of simvastatin and ciclosporin A did not affect the single or repeated dose PK of alitretinoin. The strong CYP3A4/PgP inhibitor ketoconazole led to significant increases in both AUC and C(max) values for alitretinoin. CONCLUSIONS: Single and repeated doses of alitretinoin do not alter the PK of ciclosporin A and ketoconazole. Simvastatin levels were slightly but significantly reduced by co-administration of alitretinoin. Substrates of CYP3A4 did not affect the PK of alitretinoin. However, ketoconazole significantly increased the plasma levels of alitretinoin, therefore, co-administration with CYP3A4 inhibitors such as ketoconazole may require a dose reduction of alitretinoin.

Clinical evaluation of a novel population-based regression analysis for detecting glaucomatous visual field progression.

BACKGROUND: The distinction of real progression from test variability in visual field (VF) series may be based on clinical judgment, on trend analysis based on follow-up of test parameters over time, or on identification of a significant change related to the mean of baseline exams (event analysis). The aim of this study was to compare a new population-based method (Octopus field analysis, OFA) with classic regression analyses and clinical judgment for detecting glaucomatous VF changes. PATIENTS AND METHODS: 240 VF series of 240 patients with at least 9 consecutive examinations available were included into this study. They were independently classified by two experienced investigators. The results of such a classification served as a reference for comparison for the following statistical tests: (a) t-test global, (b) r-test global, (c) regression analysis of 10 VF clusters and (d) point-wise linear regression analysis. RESULTS: 32.5 % of the VF series were classified as progressive by the investigators. The sensitivity and specificity were 89.7 % and 92.0 % for r-test, and 73.1 % and 93.8 % for the t-test, respectively. In the point-wise linear regression analysis, the specificity was comparable (89.5 % versus 92 %), but the sensitivity was clearly lower than in the r-test (22.4 % versus 89.7 %) at a significance level of p = 0.01. A regression analysis for the 10 VF clusters showed a markedly higher sensitivity for the r-test (37.7 %) than the t-test (14.1 %) at a similar specificity (88.3 % versus 93.8 %) for a significant trend (p = 0.005). In regard to the cluster distribution, the paracentral clusters and the superior nasal hemifield progressed most frequently. CONCLUSIONS: The population-based regression analysis seems to be superior to the trend analysis in detecting VF progression in glaucoma, and may eliminate the drawbacks of the event analysis. Further, it may assist the clinician in the evaluation of VF series and may allow better visualization of the correlation between function and structure owing to VF clusters.

Age dependence of plasma endothelin levels in glaucoma patients.

The aim of the study was to investigate the endothelin-1 (ET-1) plasma level and its age dependence in patients with normal tension glaucoma (NTG), high tension glaucoma (HTG), and healthy controls. In blood samples from 35 NTG patients, 34 HTG patients, and 36 controls, ET-1 plasma levels were determined by enzyme-linked immunosorbent assay (ELISA). After adjustment for age and gender, the mean ET-1 levels were found to be similar in all three study groups. The age dependency however was highest in NTGs and significantly different from that of the controls. For the HTGs, this dependence was weaker and not significantly different from that of the controls. Our findings suggest that age had a significantly greater influence on ET plasma level in the NTG patients than in the HTG patients and controls. This supports previous reports indicating that ET plays a role in the pathogenesis of glaucoma, and in particular normal NTG.

Comet assay analysis of single-stranded DNA breaks in circulating leukocytes of glaucoma patients.

PURPOSE: To investigate the amount of single-stranded DNA breaks in circulating leukocytes of primary open-angle glaucoma (POAG) patients. METHODS: A comparative quantification of DNA breaks was performed in circulating leukocytes of POAG patients and healthy controls. The following groups of subjects were compared: (1) POAG patients having primary vascular dysregulation (PVD), (2) POAG patients without PVD, (3) healthy controls with PVD, and (4) healthy controls without PVD. The damage to DNA resulting in single-stranded breaks was assessed by means of the alkaline comet assay in which the damaged DNA migrates out of the nucleus forming a tail, which can be quantified using image analysis. Damage was quantified as the comet tail moment, which represents the extent of DNA damage in individual cells. RESULTS: Leukocytes of POAG patients exerted a significantly higher amount of comet tails, which are indicative of DNA damage, in comparison to control leukocytes (p<0.001). DNA breaks occurred particularly in the subgroup of POAG patients with PVD in comparison to glaucoma patients without PVD (p=0.002). In the control group, there was no significant difference between controls with PVD and controls without PVD (p=0.86). CONCLUSIONS: POAG patients with PVD have a significantly higher rate of DNA breaks than both POAG patients without PVD and healthy controls with and without PVD.

Screening of gestational diabetes mellitus in early pregnancy by oral glucose tolerance test and glycosylated fibronectin: study protocol for an international, prospective, multicentre cohort trial.

INTRODUCTION: As the accurate diagnosis and treatment of gestational diabetes mellitus (GDM) is of increasing importance; new diagnostic approaches for the assessment of GDM in early pregnancy were recently suggested. We evaluate the diagnostic power of an 'early' oral glucose tolerance test (OGTT) 75 g and glycosylated fibronectin (glyFn) for GDM screening in a normal cohort. METHODS AND ANALYSIS: In a prospective cohort study, 748 singleton pregnancies are recruited in 6 centres in Switzerland, Austria and Germany. Women are screened for pre-existing diabetes mellitus and GDM by an 'early' OGTT 75 g and/or the new biomarker, glyFn, at 12-15 weeks of gestation. Different screening strategies are compared to evaluate the impact on detection of GDM by an OGTT 75 g at 24-28 weeks of gestation as recommended by the International Association of Diabetes and Pregnancy Study Groups (IADPSG). A new screening algorithm is created by using multivariable risk estimation based on 'early' OGTT 75 g and/or glyFn results, incorporating maternal risk factors. Recruitment began in May 2014. ETHICS AND DISSEMINATION: This study received ethical approval from the ethics committees in Basel, Zurich, Vienna, Salzburg and Freiburg. It was registered under http://www.ClinicalTrials.gov (NCT02035059) on 12 January 2014. Data will be presented at international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02035059.

Multiple primary neoplasms in childhood: data from the German Children's Cancer Registry.

The German Children's Cancer Registry (GCCR) has documented all malignancies during the first 15 years of life in Germany since 1980. In a series of 20,388 cancer cases to the end of 1995, 127 children with multiple primary neoplasms up to the age of 15 years were identified. The children were monitored for 82,591 person-years with a mean observation time of 4.1 years. Relative and cumulative risk for the occurrence of second malignant neoplasms were estimated only for the first 15 years of life, as follow-up data beyond childhood are incomplete and valid data on the incidence of cancer in adolescents and adults are not available in Germany. The overall standardised incidence ratio for a second malignancy was 12.5 (95% CI: 10.4-14.9) which implies an absolute excess risk of 141.5 per 10(5). The estimated cumulative risk within 10 years after the first malignancy was 1.9% (95% CI: 1.5-2.3). It is expected that the risk will alter with prolongation of follow-up beyond childhood.

Down syndrome clusters in Germany after the Chernobyl accident.

In two independent studies using different approaches and covering West Berlin and Bavaria, respectively, highly significant temporal clusters of Down syndrome were found. Both sharp increases occurred in areas receiving relatively low Chernobyl fallout and concomitant radiation exposures. Only for the Berlin cluster was fallout present at the time of the affected meioses, whereas the Nuremberg cluster preceded the radioactive contamination by 1 month. Hypotheses on possible causal relationships are compared. Radiation from the Chernobyl accident is an unlikely factor, because the associated cumulative dose was so low in comparison with natural background. Microdosimetric considerations would indicate that fewer than 1 in 200 oocyte nuclei would have experienced an ionizing event from Chernobyl radioactivity. Given the lack of understanding of what causes Down syndrome, other than factors associated with increased maternal age, additional research into environmental and infectious risk factors is warranted.

Blood-flow velocities of the extraocular vessels in patients with high-tension and normal-tension primary open-angle glaucoma.

PURPOSE: To evaluate blood-flow parameters in three different groups of patients with primary open-angle glaucoma. METHODS: Hemodynamic parameters in the ophthalmic artery, central retinal artery, central retinal vein, and lateral and medial short posterior ciliary arteries were evaluated by color Doppler imaging in 237 patients with primary open-angle glaucoma and 124 age-matched normal control subjects. Group A consisted of 56 patients with primary open-angle glaucoma with treated intraocular pressure higher than 20 mm Hg; group B, of 103 patients with primary open-angle glaucoma with progression of glaucomatous damage despite intraocular pressure of 21 mm Hg or less; and group C, of 78 patients with normal-tension glaucoma. RESULTS: All patients showed a significant decrease in end-diastolic velocities (P < .01) and a significant increase in resistivity index (P < .05) in all arteries measured. Peak-systolic velocities were normal in the ophthalmic artery in all three groups. In the central retinal artery and the short posterior ciliary arteries, however, patients in groups B and C had significantly reduced peak-systolic velocity (P < .05) compared with normal control subjects. Peak-systolic velocity in group A did not differ significantly from that of normal control subjects. Maximal and minimal blood-flow velocities in the central retinal vein were significantly lower in groups B and C (P < .001) compared with normal control subjects. In group A, only minimal blood-flow velocity was significantly reduced (P < .05). CONCLUSIONS: Hemodynamic parameters in the extraocular vessels are altered in patients with glaucoma. Reduced blood-flow velocities may be secondary as well as contributory to glaucomatous damage.

Blood flow velocity in the extraocular vessels in chronic smokers.

AIMS: To determine blood flow velocity in the extraocular vessels in healthy, chronic smokers and to compare these blood flow velocities with those of healthy non-smokers. METHODS: In 46 healthy chronic smokers and 189 healthy non-smokers, peak systolic velocity (PSV), end diastolic velocity (EDV), and the resistivity index (RI) were measured in the ophthalmic artery (OA), central retinal artery (CRA), lateral short posterior ciliary artery (LPCA), and medial short posterior ciliary artery (MPCA) by means of a colour Doppler device, Siemens Quantum 2000. The maximal (max) and minimal (min) velocities were measured in the central retinal vein (CRV). Only one eye was measured in each subject, and right and left eyes were chosen randomly. Blood flow velocities were compared with one way MANOVA and t tests. The influence of age, sex, systolic and diastolic blood pressure, as well as heart rate on blood flow velocity and RI were evaluated by an analysis of covariance. The potential differences of the influence of the covariables on blood flow variables in smokers and non-smokers were tested by calculating the interactions. RESULTS: In the majority of measured vessels blood flow velocity was higher in smokers than in non-smokers. This difference was statistically significant in the OA, CRV, and LPCA. The RI indices were equal or slightly lower in smokers. Furthermore, smokers had significantly lower systolic and diastolic blood pressure. Heart rate was higher in smokers but this difference did not reach statistical significance. CONCLUSIONS: Colour Doppler measurements may differ significantly in smokers compared with non-smokers. Therefore, smoking habits should be considered when interpreting colour Doppler imaging results, and comparing different groups of diseased or healthy subjects.

Variations in the blood flow of the human optic nerve head.

Blood flow in various tissues of the body shows spontaneous variations. The purpose of this study was to analyze variations over time in the blood flow of the optic nerve head. Blood flow was measured by the laser Doppler flowmeter (LDF) in 12 healthy volunteers, and analyzed by spectral Fourier analysis. The LDF technique allows continuous measurement of flow, volume, and velocity in the microcirculation of the optic nerve head. We found variations expressed in cycles per minute (c/min) at frequencies characteristic of vasomotion (< 10 c/min) of breathing, and of cardiac pulsation. Oscillations at frequency < 10 c/min predominated in volume in all subjects and in flow in all but one. Variations in velocity of 60-90 c/min were identified in 10 of the 12 volunteers. Oscillations in the range of breathing frequency made the smallest contribution to changes in blood flow. Fluctuations in the frequency range of 5 c/min and lower were observed most frequently, and the majority of subjects showed fluctuations of several frequencies. Our results provide evidence that blood flow in the human optic nerve head presents some characteristics already known from the general physiology of the microcirculation.

Assessment of a new Goldmann applanation tonometer.

BACKGROUND/AIMS: The classic Goldmann applanation tonometer (GAT) has been further developed by Haag-Streit International. The applanation principle has been retained, while the internal force transmission and the pressure gauging have been optimised, the display of results digitised. The authors compared the GAT standard with the new GAT digital. METHODS: Four fixed tonometer pairs were used. The protocol included: non-contact pachymetry, slit-lamp examination, three consecutive measurements with each tonometer with a 5 min interval in between, check for side effects in 15 min. Three groups (intraocular pressure (IOP) levels) were defined: (1) IOP ≤ 16; (2) IOP>16 and <23; (3) IOP ≥ 23 mm Hg. RESULTS: 125 Patients (250 eyes) were evaluated. IOP (mm Hg), GAT standard versus GAT digital, for the rights eyes was: Group 1: 12.94 ± 0.55 versus 13.11 ± 0.53, p=0.71. Group 2: 18.26 ± 0.59 versus 18.03 ± 0.52, p=0.53; Group 3: 30.28 ± 0.48 versus 30.42 ± 0.41, p=0.97; all right eyes: 17.48 ± 7.48 versus 17.73 ± 7.4, p=0.99. For the left eyes, there was no significant difference, either. The correlation was very good and was not influenced by the IOP level. The Pearson coefficient for the right eye was 0.985, and for the left eye 0.994. In the Bland-Altman analysis, although there were two single readings that differed by as much as 5 mm Hg, GAT digital measures showed almost no skew, and the mean difference was 0.03 ± 1.23 mm Hg (n=250). A multiple regression analysis showed no influence of order of measurement, eyeside or pachymetry. CONCLUSIONS: The new GAT digital is as reliable and safe as GAT standard. IOP values correlate well. It offers a digitised display and a wireless transfer of data. The display of values up to the first decimal digit is not necessarily associated with a more precise measurement, but may offer an additional comfort compared with the 2 mm Hg scale of the classic GAT.