Performance of the AsperGenius® PCR assay for detecting azole resistant Aspergillus fumigatus in BAL fluids from allogeneic HSCT recipients: A prospective cohort study from Essen, West Germany.

In this study a commercially available multiplex real-time PCR (AsperGenius®) was evaluated for its efficacy in detecting Aspergillus fumigatus and azole resistance markers in comparison with conventional culture methods and galactomannan (GM) testing from BAL fluids in allogeneic HSCT recipients. Between January 2015 and May 2017 100 allogeneic HSCT recipients with pulmonary infiltrates and suspicion of invasive fungal infection were recruited to the study from a tertiary care center in Germany. BAL fluid was routinely assessed using the following diagnostic tests: AsperGenius® PCR assay, GM testing (cut-off: 1.0) and conventional culture. Susceptibility testing of azoles was performed by using Etest and, in case presenting elevated MICs, PCR for mutations in the cyp51A gene was carried out. Criteria of EORTC/MSG were used to classify the patients for invasive fungal disease. According to the EORTC/MSG criteria 23 patients presented with probable invasive aspergillosis (IA). Aspergillus PCR showed a sensitivity of 65% for probable IA cases. A combination of PCR and GM results in BAL displayed a sensitivity of 96% (22/23) and 100% specificity. Mutations in the cyp51A gene were detected by PCR in three cases (3/23; 13%) which were also found resistant with the culture method. In one case a Y121F/T289A mutation and in two cases a L98H were found. The combination of a commercial Aspergillus PCR assay and GM testing from BAL demonstrated a high sensitivity and specificity for diagnosing IA in allogeneic HSCT recipients. The Aspergillus PCR assay was not superior in detecting azole resistant A. fumigatus compared to culture.

Prevalence and characterization of azole-resistant Aspergillus fumigatus in patients with cystic fibrosis: a prospective multicentre study in Germany.

Objectives: Aspergillus fumigatus is the most prevalent filamentous fungus in the respiratory tract of patients with cystic fibrosis (CF). The aim of this prospective multicentre study was to investigate the prevalence of azole-resistant A. fumigatus (ARAF) in respiratory secretions from CF patients across Germany and to characterize ARAF isolates by phenotypic and molecular methods. Methods: Twelve tertiary care centres from Germany participated in the study. In total, 2888 A. fumigatus isolates from 961 CF patients were screened for ARAF by using azole-containing agar plates. Antifungal susceptibility testing of isolates was performed by broth microdilution according to EUCAST guidelines. Analysis of mutations mediating resistance was performed using PCR and sequencing of the cyp51A gene. Furthermore, genotyping by microsatellite PCR was performed. Results: Of a total of 2888 A. fumigatus isolates, 101 isolates from 51 CF patients were found to be azole resistant (prevalence per patient 5.3%). The Essen centre had the highest prevalence (9.1%) followed by Munich (7.8%), Münster (6.0%) and Hannover (5.2%). Most ARAF isolates (n = 89) carried the TR34/L98H mutation followed by eight G54E/R, one TR46/Y121F/T289A and one F219S mutation. In two isolates no mutation was found. Genotyping results showed no major clustering. Forty-five percent of CF patients with ARAF had previously received azole therapy. Conclusions: This is the first multicentre study analysing the prevalence of ARAF isolates in German CF patients. Because of a resistance rate of up to 9%, susceptibility testing of A. fumigatus isolates from CF patients receiving antifungal treatment should be part of standard diagnostic work-up.

The influence of AMH on IVF success.

PURPOSE: Anti-Müllerian hormone has a regulative function in the activation of folliculogenesis and an influence on atresia rate. It is considered a marker for the ovarian reserve. We know that a relationship exists between AMH levels and oocyte retrieval numbers, antral follicle count, pregnancy rates and birth rates. The role of AMH as an efficient prognostic factor in determining the probability of pregnancy has been largely discussed in the literature. The aim of this study is to determine the role age and AMH levels play in success rates of IVF/ICSI therapies. To date, the sample group we examined was one of the biggest ever included in a single study of the subject. METHODS: All patients who underwent an IVF/ICSI treatment with FSH stimulation in the Wiesbaden Kinderwunschzentrum between 2003 and 2010, were no older than 44 years old, and had an evaluation of serum AMH levels before treatment were included in this study. In total, 1287 patients were analysed retrospectively. Statistical analysis was performed with SPSS. RESULTS: Females' mean age was 34.89, ranging from 21 to 44 years. The patients underwent between 1 and 11 IVF cycles. Younger women had significantly higher AMH levels (p = 0.001). Patients with higher AMH levels had significantly lower break-off rates (p < 0.0005) and a significantly higher number of oocytes retrieved (p < 0.0005). Higher levels of AMH corresponded to higher pregnancy rates (p = 0.017). AMH levels do not influence pregnancy rates in younger patients (<36 years). CONCLUSIONS: AMH is a useful parameter that should be measured before performing an IVF/ICSI treatment. In younger patients, AMH levels do not predict pregnancy outcomes. In patients older than 36 years, AMH can be used as a prognostic factor. Even when a woman's AMH levels are too low to be detected, she still an acceptable chance of becoming pregnant.

A first-in-human study of PDC31 (prostaglandin F2α receptor inhibitor) in primary dysmenorrhea.

STUDY QUESTION: What is the safe and pharmacodynamically active dose range for PDC31 (prostaglandin F2α receptor inhibitor) in patients with primary dysmenorrhea (PD)? SUMMARY ANSWER: The 1 mg/kg/h dose of PDC31 appears to be safe and potentially effective in reducing intrauterine pressure (IUP) and pain associated with excessive uterine contractility when given as a 3-h infusion in patients with PD. WHAT IS KNOWN ALREADY: PDC31 has previously been shown to reduce the duration and strength of PGF2α-induced contractions in human uterine myometrial strip models and to delay delivery in animal models of preterm labor. STUDY DESIGN, SIZE, DURATION: This was a prospective, multi-center, dose-escalating first-in-human Phase I study conducted from March 2011 to June 2012. A total of 24 women with PD were enrolled and treated with one of five doses (0.01, 0.05, 0.15, 0.3, 0.5 and 1 mg/kg/h) of PDC31 given as a 3-h infusion. Patients were observed for a further 24 h. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study was conducted at four hospitals in Europe in non-pregnant, menstruating women with PD. Women with PD (n = 24) received PDC31 infused over 3 h within 8-10 h of the onset of menstruation. IUP and pain monitoring through the visual analog scale (VAS) was assessed prior to, during and following the infusion. Patients were observed for dose-limiting toxicities and other adverse events. Pharmacokinetic samples were also taken to profile the drug. MAIN RESULTS AND THE ROLE OF CHANCE: A 3-h infusion of PDC31 was safe up to and including doses of 1 mg/kg/h. Most adverse events were mild (n = 15; 83.3%) and not considered associated with PDC31 (n = 14; 77.8%). PDC31 infusion decreased uterine activity based on IUP and pain (VAS) scores. IUP was decreased by 23% over all dose levels, reaching a minimum at 135-150 min. There appeared to be a dose-dependent effect on IUP, with the high dose group (1 mg/kg/h) showing the largest decrease in IUP. There was a statistically significant linear dose-effect and concentration-effect relationship for several IUP parameters over the evaluation period of 60-180 min. A dose differentiating effect on pain was seen with the two highest doses. PDC31 demonstrated uncomplicated, linear pharmacokinetics with a terminal half-life of ∼2 h. LIMITATIONS, REASONS FOR CAUTION: This was a first-in-human study and exposure to PDC31 was limited for safety reasons. As such, pharmacodynamic parameters were assessed at a two-sided Type I error of 20%, an appropriate level for the exploratory nature of this study without a placebo control arm. This limited the chance of false positive findings to one in five. WIDER IMPLICATIONS OF THE FINDINGS: Like PD, preterm labor is associated with prostaglandin-mediated uterine contractions; therefore, the findings of this study support further development of PDC31 as a treatment for both PD and preterm labor. STUDY FUNDING/COMPETING INTERESTS: This work was funded by PDC Biotech GmbH, Vienna, Austria. B.B., R.M.L., L.W., R.J.S., K.J.B. and C.F.S. received reimbursement for the conduct of this study from PDC Biotech GmbH. W.H., M.S. and R.P.S. are paid consultants for PDC Biotech GmbH. P.G. is a paid consultant and shareholder of PDC Biotech GmbH. TRIAL REGISTRATION NUMBER: NCT01250587 at www.clinicaltrials.gov.

Adjuvant endocrine treatment with medroxyprogesterone acetate or tamoxifen in stage I and II endometrial cancer--a multicentre, open, controlled, prospectively randomised trial.

Endometrial cancer is a hormone-dependent disease and therefore an adjuvant hormonal therapy might improve the outcome in the early stages of the disease. Between 1983 and 1989, we conducted a randomised trial of 388 patients who received either medroxyprogesterone acetate (MPA) (n=133) or tamoxifen (n=121) orally for 2 years, or were observed only (n=134) after surgical therapy. The aim was to evaluate whether an adjuvant treatment can improve disease-free and overall survival rates. After a median follow-up period of 56 months (range 3-199 months), we observed no differences in the disease-free and overall survival rates for the tamoxifen group compared with the control or the MPA group. Side-effects were more frequent and severe in the MPA-group than in the tamoxifen group. In patients with early endometrial cancer, adjuvant endocrine treatment did not significantly improve the outcome. However, tamoxifen did have some beneficial effects on coexisting morbidity.

Inverse correlation between baseline inhibin B and FSH after stimulation with GnRH: a study of serum levels of inhibin A and B, pro alpha-C and activin A in women with ovulatory disturbances before and after stimulation with GnRH.

OBJECTIVE: Interest has focused recently on the influences of the polypeptide factors inhibin and activin on the selective regulation of the pituitary secretion of gonadotropins. DESIGN: Measurement of the concentrations of inhibin-related proteins in relation to the changes in pituitary gonadotropin (FSH, LH) parameters, after GnRH stimulation with a bolus injection of 100 microg gonadorelin, in 19 women with ovulatory disturbances. METHODS: Serum levels of inhibin A and B, activin A, and pro alpha-C were measured using sensitive ELISA kits. RESULTS: Within 60 min after GnRH stimulation, FSH values doubled from 5 to 10 mU/ml (P < 0.001). LH increased 12-fold from 2 to 24 mU/ml (P < 0.001). Activin A showed a significant decrease from 0.47 to 0.36 ng/ml (P < 0.001), whereas pro alpha-C increased from 127 to 156 pg/ml (P = 0.039). The median inhibin A concentration did not show a significant change between baseline and the 60 min value, whereas inhibin B was characterized by a minor, but not significant, increase in the median from 168 to 179 pg/ml (P = 0.408). A significant inverse correlation (P = 0.014) with a mean coefficient of correlation of 0.5516 was found, demonstrating a strong relationship between high inhibin B baseline levels and a small increase of FSH after 60 min. CONCLUSION: Our results show an interesting correlation between the baseline inhibin B and the change in FSH before and after GnRH stimulation. A high baseline inhibin B implies only a minor increase of FSH after 60 min.

Concentrations of inhibins and activin in women undergoing stimulation with recombinant follicle-stimulating hormone for in vitro fertilization treatment.

OBJECTIVE: To investigate the influence of human recombinant follicle-stimulating hormone (FSH) on circulating serum concentrations of the ovarian proteohormones inhibin A, inhibin B, pro alpha-C, and activin A and serum levels of estradiol after down-regulation with GnRH analogue. DESIGN: Serum concentrations of ovarian proteohormones and estradiol. SETTING: Academic clinical practice. PATIENT(S): 30 women who underwent assisted reproductive techniques. INTERVENTION(S): Blood samples were analyzed for inhibin A, inhibin B, pro alpha-C, activin A, and estradiol during IVF treatment at points coinciding with pituitary down-regulation, stimulation with recombinant FSH, ovulatory triggering, and the luteal phase of the cycle. RESULT(S): Activin A levels did not change with recombinant FSH stimulation. In women with a sonographically detected leading follicle >17 mm in diameter, levels of inhibin A, pro alpha-C, and estradiol increased significantly (P<.05). The increase in inhibin B level was not statistically significant. In patients without adequate follicle development during FSH stimulation, serum levels of inhibins remained low and did not significantly deviate from values measured before stimulation. CONCLUSION(S): Inhibin A and pro alpha-C are effective markers of follicular development and may be effective additions to estradiol as a marker.

Atrial natriuretic peptide (ANP) in preeclampsia-like syndrome in a rat model.

The pathophysiology of preeclampsia has not been fully clarified. A variety of factors have been implicated with this disease including vasoactive peptides and hormones during the last 20 years. Inadequate generation of atrial natriuretic peptide (ANP) has been one of the mechanisms discussed as to possibly contribute to the development of hypertension. In human pregnancy multiple studies of ANP-plasma-concentration in normal or hypertensive pregnancies showed conflicting results. The complexity of the clinical findings of hypertension in pregnancy makes it very difficult to carry out comparative clinical and biochemical studies in humans. In an animal experience genetic as environmental influences could be excluded. Therefore, the present study shows an experimental preeclampsia-like syndrome in the rat by reduction of the utero-placental flow. We observed a significant increase of plasma ANP in pregnant rats with experimentally induced hypertension. Furthermore, our results suggest that the ventricles could be an important source of ANP gene expression.

Early postpartum hyponatremia in a patient with transient Sheehan's syndrome.

In modern day health care, Sheehan's syndrome is a rare disorder affecting the postpartum period. We present a case of a 33-year-old woman with atonic hemorrhage developing a transient Sheehan's syndrome associated with hyponatremia six days postpartum. Evaluation of cranial computer tomography and magnetic resonance imaging of the pituitary demonstrated normal finding. Immediate replacement therapy using sodium, chloride, hydrocortisone, fludrocortisone and levothyroxine revealed regression of the Sheehan's syndrome to complete recovery. The present report shows that Sheehan's syndrome can be associated with hyponatremia and illustrates the need to include hyponatremia as an initial symptom in the differential diagnosis of Sheehan's syndrome.

[Local gastric fibrinolysis]. / Untersuchungen zur lokalen Fibrinolyse des Magens.

Local fibrinolytic activity was studied in normal and hemorrhagic gastric juice and in the gastric wall of men and pigs. This activity was definitely higher in hemorrhagic juice than in normal gastric juice, and its probably released from hemolyzed erythrocytes and mucosal lesions of the gastric wall.

[Perioperative antibiotic prophylaxis in elective splenectomy. A randomized prospective study]. / Perioperative Antibioticaprophylaxe bei der elektiven Splenektomie. Eine randomisierte, prospektive Studie.

After elective splenectomy septic complications in the early postoperative period occur up to 45%. In a prospective, randomised, controlled study of 61 patients the incidence of postoperative infections with and without prophylactic use of an antibiotic was compared. 61 patients undergoing elective splenectomy were divided into two groups. 28 patients were operated without any antibiotic, 33 patients were given 3 X 1500 mg Cefuroxim (Zinazef) for three days, starting 1 h prior to the operation. Infections of the urinary tract and the lung were excluded preoperatively. With a standardized program we searched for intraabdominal abscesses, infections of the lung, the urinary system and the abdominal incision postoperatively. No fatal complication occurred. A significant reduction in total septic complication rate (p less than 0.01) and in pneumonia was found as well in benign as in malignant disease. The study shows, that the apparently disturbed immunological defense following splenectomy can be improved by the prophylactic use of antibiotics.

[Splenectomy in Werlhof disease without thrombocyte substitution. Prospective study of 7 consecutive cases]. / Splenektomie bei Morbus Werlhof ohne Thrombocytensubstitution. Eine prospektive Untersuchung an sieben konsekutiven Fällen.

As a prophylaxis against the risk of postoperative bleeding platelet mass transfusions or transfusions of whole fresh blood are recommended for splenectomy in chronic idiopathic thrombocytopenic purpura. As the efficacy of this treatment is uncertain, seven consecutive patients with platelet counts of 4000/mm3 (2000-16000) were splenectomized without this prophylaxis. Platelet counts rose to 152500/mm3 (70000--305000) 18 h after operation, in every case the critical lower limit of 50000 was exceeded. Apart from one case of transient fever of undetected origin and one small pleural effusion there were no complications. Even in patients with extremely low platelet counts splenectomy can be performed without platelet mass transfusion.

[Initial clinical experiences with heterotopic autotransplantation of the spleen]. / Erste klinische Erfahrungen mit der heterotopen Autotransplantation der Milz.

Since April 1980 ruptured spleens have been removed in seven patients (6-43 years old) and reimplanted into the omentum majus using a new operative technique. This procedure took about 15 min. Two patients died because of associated trauma to other organs. There were no complications due to this autologous, heterotopic transplantation. Four months after the operation elektrophoresis of immunglobulins, Howell-Jolly bodies and "pitted" RBCs were totally normalized. A 99mTc-scintigram with human albumin-millimicrospheres showed an intact phagocytosis and ingestion by the transplant. Therefore, good protection against infection is to be expected. The heterotopic autotransplantation of the spleen should be used in cases of splenic trauma if the clinical situation demands total splenectomy.

The influence of autonomous nervous activity on total and regional gastric blood flow.

Using 8 mu radioactive microspheres total and regional gastric blood flow were measured in dogs under electrical splanchnic stimulation (SS), following splanchnicectomy (SE), under electrical stimulation of the vagal truncs (VS) and following truncal vagotomy (VE). The values were compared to controls and were taken while cardiac output (CO) and mean aortic pressure ( AOBP ) were registered. Total GBF was 16 +/- 4 ml/100g/min. in 8 animals. Regional flows were highest in the mucosa of corpus and fundus (35 +/- 7 and 27 +/- 6 ml/100g/min.) and lowest in the seromuscularis (4 +/- 1 ml/100g/min.) SS decreased total GBF to 7 +/- 2 ml/100g/min. and this was due to a most dramatic fall in corpus and fundus mucosal flow by 75%. In contrast SE increased total GBF to 30 +/- 11 and regional corpus mucosal flow achieved 85 +/- 24 ml/100g/min. Blood flow changes under VS were similar to those following SE but were less elevated. In the same manner flow reduction following VE was similar to the changes seen after SS but in average less profound. CO and AOBP increased during SS (less than 30% of control) but were almost the same for SE, VS and VE.

How to achieve total gastric sympathectomy.

Experimental examinations on acute, stress induced gastric ulcers have shown the outstanding role of the sympathetic innervation in the pathogenesis of this ischemic disease. As reduction of sympathetic tonus resulted in a significant prophylaxis against "stress ulcers", further experimental work was done to achieve total but selective gastric sympathectomy. In a histomorphological study in dogs (Method: Hillarp and Falck in the modification of Heene ) the effects of three different surgical procedures on gastric sympathetic denervation were investigated: 1. Selective proximal vagotomy (= SPV, 8 dogs) 2. SPV and periarterial denervation of the main gastric arteries with severance of the gastrolineal ligament (= PASD , 8 dogs) 3. PASD alone (7 dogs) Selective proximal vagotomy resulted in a sympathetic denervation of major parts of the right site of the fundus and corpus. Following selective proximal vagotomy with periarterial denervation ( PASD ) there was a complete sympathetic denervation of the entire stomach. Only a minimal area of resting sympathetic innervation was observed on the esophago-cardial border when periarterial denervation ( PASD ) was performed alone.

Success Rate of Inseminations Dependent on Maternal Age? An Analysis of 4246 Insemination Cycles.

Intrauterine insemination (IUI) has latterly become less important in reproductive medicine. The aim of this retrospective analysis was to identify and evaluate the success rates of repeated insemination cycles in women of different ages. All women who underwent intrauterine insemination in the Wiesbaden Fertility Clinic between 1998 and 2010 were included in the analysis. Additional inclusion criteria were: not more than 45 years old, previous FSH stimulation and slight to moderate subfertility of the male partner. A total of 4246 insemination cycles in 1612 patients were included in the analysis. The average number of IUI cycles per patient was 2.24 (1-14). Patient age ranged from 19 to 45 years (mean: 33.9 years). Logistic regression analysis showed a drop in pregnancy rates with increasing age (p = 0.000). However, for the first three cycles the pregnancy rates for women aged 40 and 41 did not differ from those of women aged between 35 and 39 years. Overall pregnancy rates were stable in women up to the age of 40, even after several insemination cycles (7.5 and 10 %). Insemination is therefore still an effective procedure in selected patients. Stable pregnancy rates were recorded even after more than 3 cycles. After 3 cycles, the success rates for women aged 40 and 41 did not differ from those of women below the age of 40.