Tralokinumab plus topical corticosteroids for the treatment of moderate-to-severe atopic dermatitis: results from the double-blind, randomized, multicentre, placebo-controlled phase III ECZTRA 3 trial.

BACKGROUND: Tralokinumab is a fully human monoclonal antibody that specifically neutralizes interleukin-13, a key driver of atopic dermatitis (AD). OBJECTIVES: To evaluate the efficacy and safety of tralokinumab in combination with topical corticosteroids (TCS) in patients with moderate-to-severe AD who were candidates for systemic therapy. METHODS: This was a double-blind, placebo plus TCS controlled phase III trial. Patients were randomized 2 : 1 to subcutaneous tralokinumab 300 mg or placebo every 2 weeks (Q2W) with TCS as needed over 16 weeks. Patients who achieved an Investigator's Global Assessment (IGA) score of 0/1 and/or 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16 with tralokinumab were rerandomized 1 : 1 to tralokinumab Q2W or every 4 weeks (Q4W), with TCS as needed, for another 16 weeks. RESULTS: At week 16, more patients treated with tralokinumab than with placebo achieved IGA 0/1: 38·9% vs. 26·2% [difference (95% confidence interval): 12·4% (2·9-21·9); P = 0·015] and EASI 75: 56·0% vs. 35·7% [20·2% (9·8-30·6); P < 0·001]. Of the patients who were tralokinumab responders at week 16, 89·6% and 92·5% of those treated with tralokinumab Q2W and 77·6% and 90·8% treated with tralokinumab Q4W maintained an IGA 0/1 and EASI 75 response at week 32, respectively. Among patients who did not achieve IGA 0/1 and EASI 75 with tralokinumab Q2W at 16 weeks, 30·5% and 55·8% achieved these endpoints, respectively, at week 32. The overall incidence of adverse events was similar across treatment groups. CONCLUSIONS: Tralokinumab 300 mg in combination with TCS as needed was effective and well tolerated in patients with moderate-to-severe AD.

Anxiety-associated and separation distress-associated behaviours in Angelman syndrome.

BACKGROUND: Anxiety is considered a 'frequent' feature in the clinical criteria for Angelman syndrome; however, the nature and severity of anxiety symptoms have not been well characterised in this population. Anxiety behaviours, especially in response to separation from a preferred caregiver, have been described clinically but have not yet been explored empirically. METHOD: This study used a combination of standardised and clinician-derived survey items to assess the frequency, nature and severity of behaviours associated with anxiety and separation distress in 100 individuals with Angelman syndrome. Family (e.g. income and maternal education) and individual (e.g. age, sex, genetic subtype, sleep difficulties and aggressive behaviours) variables were also gathered to assess possible predictors of higher anxiety levels. Approximately half of the sample was seen in clinic and assessed with standardised measures of development and daily functioning, allowing for an additional exploration of the association between anxiety symptoms and extent of cognitive impairment. RESULTS: Anxiety concerns were reported in 40% of the sample, almost 70% were reported to have a preferred caregiver and over half displayed distress when separated from that caregiver. Individuals with the deletion subtype and individuals who are younger were less likely to have anxiety behaviours. Sleep difficulties and aggressive behaviour consistently significantly predicted total anxiety, the latter suggesting a need for future studies to tease apart differences between anxiety and aggression or anger in this population. CONCLUSIONS: Anxiety concerns, especially separation distress, are common in individuals with Angelman syndrome and represent an area of unmet need for this population.

Secukinumab demonstrates high sustained efficacy and a favourable safety profile in patients with moderate-to-severe psoriasis through 5 years of treatment (SCULPTURE Extension Study).

BACKGROUND: Secukinumab, a fully human monoclonal antibody that selectively neutralizes IL-17A, has been shown to have significant efficacy and a favourable safety profile in the treatment of moderate-to-severe psoriasis and psoriatic arthritis. OBJECTIVE: To assess the efficacy and safety of secukinumab through 5 years of treatment in moderate-to-severe psoriasis. METHODS: In the core SCULPTURE study, Psoriasis Area and Severity Index (PASI) 75 responders at Week 12 continued receiving subcutaneous secukinumab until Year 1. Thereafter, patients entered the extension phase and continued treatment as per the core trial. Treatment was double-blinded until the end of Year 3 and open-label from Year 4. Here, we focus on the 300 mg fixed-interval (every 4 weeks) treatment, the recommended per label dose. Efficacy data are primarily reported as observed, but multiple imputation (MI) and last observation carried forward (LOCF) techniques were also undertaken as supportive analyses. RESULTS: At Year 1, 168 patients entered the extension study and at the end of Year 5, 126 patients completed 300 mg (every 4 weeks) treatment. PASI 75/90/100 responses at Year 1 (88.9%, 68.5% and 43.8%, respectively) were sustained to Year 5 (88.5%, 66.4% and 41%). PASI responses were consistent regardless of the analysis undertaken (as observed, MI, or LOCF). The average improvement in mean PASI was approximately 90% through 5 years compared with core study baseline. DLQI (dermatology life quality index) 0/1 response also sustained through 5 years (72.7% at Year 1 and 65.5% at Year 5). The safety profile of secukinumab remained favourable, with no cumulative or unexpected safety concerns identified. CONCLUSION: Secukinumab 300 mg treatment delivered high and sustained levels of skin clearance and improved quality of life through 5 years in patients with moderate-to-severe psoriasis. Favourable safety established in the secukinumab phase 2/3 programme was maintained through 5 years.

Secukinumab sustains good efficacy and favourable safety in moderate-to-severe psoriasis after up to 3 years of treatment: results from a double-blind extension study.

BACKGROUND: Secukinumab has demonstrated significant efficacy with a good safety profile through 1 year in plaque psoriasis. Given the chronic nature of this disease, long-term follow-up is needed to evaluate psoriasis therapies fully. OBJECTIVES: To determine the long-term (3-year) efficacy and safety of secukinumab in moderate-to-severe psoriasis. METHODS: Patients completing 52 weeks of secukinumab treatment in the SCULPTURE core study entered an extension in which they continued the same double-blind regimens. Dosing regimens included a fixed-interval schedule (FI; every 4 weeks) and retreatment as needed (RAN), in which patients were withdrawn from secukinumab and received placebo until the start of relapse, at which time secukinumab every 4 weeks was reinitiated. The study was registered with number NCT01640951. RESULTS: In total 168 patients receiving secukinumab 300 mg FI and 172 receiving secukinumab 300 mg RAN entered the extension. Secukinumab 300 mg FI sustained high efficacy: at the end of year 3, the proportion of responders achieving ≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90) was 63·8%, and of PASI 100 responders it was 42·6%. The mean absolute PASI remained low (2-4) from week 52 to week 152 with 300 mg FI, with approximately two-thirds of patients reporting no impact of skin disease on their lives (Dermatology Life Quality Index of 0 or 1). Improvements in overall and subscale scores on all quality-of-life instruments were well sustained. As in the core study, FI dosing was consistently more efficacious than RAN. No new safety signals were identified to year 3. CONCLUSIONS: Secukinumab 300 mg FI sustained high responses and improved quality of life with no new safety concerns through 3 years.

Constructing Ebola transmission chains from West Africa and estimating model parameters using internet sources.

During the recent Ebola crisis in West Africa, individual person-level details of disease onset, transmissions, and outcomes such as survival or death were reported in online news media. We set out to document disease transmission chains for Ebola, with the goal of generating a timely account that could be used for surveillance, mathematical modeling, and public health decision-making. By accessing public web pages only, such as locally produced newspapers and blogs, we created a transmission chain involving two Ebola clusters in West Africa that compared favorably with other published transmission chains, and derived parameters for a mathematical model of Ebola disease transmission that were not statistically different from those derived from published sources. We present a protocol for responsibly gleaning epidemiological facts, transmission model parameters, and useful details from affected communities using mostly indigenously produced sources. After comparing our transmission parameters to published parameters, we discuss additional benefits of our method, such as gaining practical information about the affected community, its infrastructure, politics, and culture. We also briefly compare our method to similar efforts that used mostly non-indigenous online sources to generate epidemiological information.

A prospective phase III, randomized, double-blind, placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis.

BACKGROUND: The interleukin-17 cytokine family plays a central role in psoriasis pathogenesis. OBJECTIVES: To evaluate the efficacy and safety of brodalumab, a human anti-interleukin-17 receptor antibody, in treating patients with moderate-to-severe plaque psoriasis. METHODS: In this phase III, double-blind, placebo-controlled study (NCT01708590; AMAGINE-1), adult patients in the U.S.A., Canada and Europe were randomized to brodalumab (140 or 210 mg) or placebo every 2 weeks (Q2W), with an additional dose at week 1, for a 12-week induction phase. At week 12, patients receiving brodalumab who achieved static Physician's Global Assessment 0 or 1 (sPGA success) were rerandomized to the placebo or induction dose. After week 16, patients with sPGA ≥ 3 were re-treated with the induction dose. After ≥ 12 weeks of retreatment, patients with sPGA 2 for ≥ 4 weeks or sPGA ≥ 3 were rescued with brodalumab 210 mg Q2W. At week 12, patients randomized to brodalumab with sPGA ≥ 2 or placebo received brodalumab 210 mg Q2W. Coprimary end points were the percentage of patients with ≥ 75% improvement in Psoriasis Area and Severity Index score (PASI 75) and sPGA success at week 12. RESULTS: There were 661 patients randomized: 220 placebo, 219 brodalumab 140 mg and 222 brodalumab 210 mg. At week 12, 60% (140 mg) and 83% (210 mg) vs. 3% (placebo) achieved PASI 75, and 54% (140 mg) and 76% (210 mg) vs. 1% (placebo) achieved sPGA success. The safety profile was considered acceptable. CONCLUSIONS: Brodalumab therapy resulted in significant clinical benefit and an acceptable safety profile in patients with moderate-to-severe plaque psoriasis.

The pandemic potential of avian influenza A(H7N9) virus: a review.

In March 2013 the first cases of human avian influenza A(H7N9) were reported to the World Health Organization. Since that time, over 650 cases have been reported. Infections are associated with considerable morbidity and mortality, particularly within certain demographic groups. This rapid increase in cases over a brief time period is alarming and has raised concerns about the pandemic potential of the H7N9 virus. Three major factors influence the pandemic potential of an influenza virus: (1) its ability to cause human disease, (2) the immunity of the population to the virus, and (3) the transmission potential of the virus. This paper reviews what is currently known about each of these factors with respect to avian influenza A(H7N9). Currently, sustained human-to-human transmission of H7N9 has not been reported; however, population immunity to the virus is considered very low, and the virus has significant ability to cause human disease. Several statistical and geographical modelling studies have estimated and predicted the spread of the H7N9 virus in humans and avian species, and some have identified potential risk factors associated with disease transmission. Additionally, assessment tools have been developed to evaluate the pandemic potential of H7N9 and other influenza viruses. These tools could also hypothetically be used to monitor changes in the pandemic potential of a particular virus over time.

In vitro and in vivo multidrug resistance reversal activity by a Betti-base derivative of tylosin.

BACKGROUND: The multidrug resistance (MDR) proteins are present in a majority of human tumours. Their activity is important to understand the chemotherapeutic failure. A search for MDR-reversing compounds was conducted among various Betti-base derivatives of tylosin. METHODS: Here, we evaluate the in vitro and in vivo P-glycoprotein (P-gp)-modulating activity of the most promising compound N-tylosil-1-alpha-amino-(3-bromophenyl)-methyl-2-naphthol (TBN) using human MDR1 gene-transfected and parental L5178 mouse lymphoma cell lines. RESULTS: In vitro experiments showed that TBN dramatically increased the P-gp-mediated cellular uptake of the fluorescent substrate rhodamine 123. Similarly, TBN was found to act as a very potent enhancer of the cytotoxicity of doxorubicin on the resistant cell line. We also provide in vivo evidence using DBA/2 mice in support for an increased tumoural accumulation of doxorubicin, without affecting its tissue distribution, resulting in an enhanced antitumoural effect. CONCLUSION: Our results suggest that TBN is a potent modulator of the P-gp membrane pump and that the compound could be of clinical relevance to improve the efficacy of chemotherapy in MDR cancers.

Fecal expression of Escherichia coli lysine decarboxylase (LdcC) is downregulated in E-cadherin negative lobular breast carcinoma.

Breast cancer is characterized by oncobiosis, the abnormal composition of the microbiome in neoplastic diseases. The biosynthetic capacity of the oncobiotic flora in breast cancer is suppressed, as suggested by metagenomic studies. The microbiome synthesizes a set of cytostatic and antimetastatic metabolites that are downregulated in breast cancer, including cadaverine, a microbiome metabolite with cytostatic properties. We set out to assess how the protein expression of constitutive lysine decarboxylase (LdcC), a key enzyme for cadaverine production, changes in the feces of human breast cancer patients (n = 35). We found that the fecal expression of Escherichia coli LdcC is downregulated in lobular cases as compared to invasive carcinoma of no special type (NST) cases. Lobular breast carcinoma is characterized by low or absent expression of E-cadherin. Fecal E. coli LdcC protein expression is downregulated in E-cadherin negative breast cancer cases as compared to positive ones. Receiver operating characteristic (ROC) analysis of LdcC expression in lobular and NST cases revealed that fecal E. coli LdcC protein expression might have predictive values. These data suggest that the oncobiotic transformation of the microbiome indeed leads to the downregulation of the production of cytostatic and antimetastatic metabolites. In E-cadherin negative lobular carcinoma that has a higher potential for metastasis formation, the protein levels of enzymes producing antimetastatic metabolites are downregulated. This finding represents a new route that renders lobular cases permissive for metastasis formation. Furthermore, our findings underline the role of oncobiosis in regulating metastasis formation in breast cancer.

[Thermachoice thermal balloon therapy--a 10-year-experience]. / Termoablace endometria systémem Thermachoice-- 10 let zkuseností.

OBJECTIVE: To evaluate the effectivness of a global method of endometrium ablation--Thermachoice (Gynecare; Johnson & Johnson) baloon therapy in treatment of excessive uterine bleeding. Our 10-year-long-experience is presented. DESIGN: Retrospective study. SETTINGS: Department of Gynecology and Obstetrics, First faculty of Medicine, Charles University and General Teaching Hospital, Prague. METHODOLOGY AND RESULTS: 109 patients were treated in our depatment from November 1997 till the end of the year 2007. The pacients were contacted personally, over the phone and by sending questinnaires. 92 women (84.4%) were included into the evaluation group after twelve month and after 5 years there were 54 women. The group was mostly formed by seriously polymorbid patients. The average age was 41.6 years. In the twelve-month-follow-up there were 38 percent amenorrheic, five years later there were 63 percent of them. 13 women (14%) ended with hysterectomy--two pacients without any connection with the operation. In 3 cases there was a therapeutic cycle failure, because the acquired intrauterine pressure was not reached. In one case of the monstrous obese woman, after a longer period form the operation there was a carcinoma of the endometrium found out. Two women after the termoablation became pregnant: the first one non-voluntarily, she decided for the arteficial abortion and then the hysterectomy, the second one, despite the fact, that she had been fully informed, underwent the IVF therapy and at the age of 37 she delivered by the Cesarian section in the 36-week-old pregnancy the healthy girl weighing 2900 gramms. With one patient--a young woman the operation was combined with uterine artery embolisation (UAE)--and that is why she was excluded. 51.5% of all operations were perfomed without general anestesia. There was no serious complication in the observed group. CONCLUSION: The big advantage of the second generation ablation methods is the possibility to realise the operation without the general anestesia and with the minimum discomfort for the patient. Another favourable circumstance was the shorter determined operating time and lower percentage of complications in comparison with the first generation methods. The big benefit is mainly for the seriously polymobid pacients.

[Sexual functions after laparoscopically assisted vaginal hysterectomy (LAVH) and total laparoscopic hysterectomy (TLH) in preoperatively asymptomatic women]. / Sexuální funkce po laparoskopicky asistované vaginální es gynek. hysterektomii (LAVH) a totální laparoskopické hysterektomii (TLH) u predoperacne asymptomatických zen.

OBJECTIVE: To find the consequences of laparoscopically assisted vaginal hysterectomy (LAVH) and total laparoscopic hysterectomy (TLH) for sexual functions in preoperatively asymptomatic women. DESIGN: Prospective study. SETTING: Department of Obstetrics and Gynecology, 1st Faculty of Medicine, Charles University and General Teaching Hospital in Prague. MATERIAL AND METHODS: In 100 women without subjective complaints hysterectomy was performed for benign uterine pathology. In all the women the uterus weighted less than 250 g, there were no salpingooophorectomies and no perioperative complications. Women were alternativelly assigned for LAVH (n = 50) or TLH (n = 50). Clinical documentation and questionnaires about sexual functions were evaluated in 87 women (in 40 women after LAVH and in 47 after TLH) 18 months after surgery or later. RESULTS: According to our findings the type of surgery did not influence the frequency of sexual activity after surgery, there was no change in sexual manners using during coitus as well as no change in preferred way how to reach the sexual arousal (clitoridally, vaginally or combined). The type of surgery did not influence frequency, quality and duration of orgasm. From all the evaluated parameters there were only two significantly different: the presence of postoperative sexual activity (positive answer in all women from LAVH group and only in 85% women from TLH group, F test, p = 0.009) and the frequency of sexual satisfaction (in terms of both increase and also decrease in TLH group chi2 8,376, p = 0.015). CONCLUSION: The type of laparoscopic hysterectomy (LAVH or TLH) does not significantly affect the sexual functions (frequency of sexual satisfaction, type of sexual arousability, intensity and duration of orgasm) in preoperatively asymptomatic women.

Uterine arteries doppler velocimetry provides 3-years follow up endometrial ablation outcome.

The aim of this study was to assess whether uterine artery Doppler velocimetry [pulsatility index (PI) and resistance index (RI)] and thickness of the endometrium (TE) are able to predict 3-year clinical outcome after endometrial ablation (EA) for dysfunctional uterine bleeding (DUB). This was a prospective, observational study of 29 women of whom 22 were amenorrhoeic (A) and 7 eumenorrhoeic (E) at the end of the first postoperative year. The PI, RI and TE were measured prior to and 1, 6 and 12 months after EA. Statistical analyses were performed using BMDP statistical software, discriminant analysis, ANOVA and T test. Using the calculated classification function (CF) with the three parameters PI, RI and TE measured 12 months after FEAT, we were able to accurately (100%) specify which of the women will have A or E in 3 years. The predictive value of PI, RI and TE has been confirmed clinically in a minimum 3-year follow-up of outcome (ranging from 36 to 72 months [mean 55]). All A and E women have stayed in the same group (A or E) during the minimum of 3 years. In conclusion we found that PI, RI and TE measured prior to EA cannot predict the outcome, however these measurements performed 1 year after FEAT can predict the duration of A or E in the 3-year follow up.

[Office hysteroscopy--state of the art]. / Soucasný stav ambulantní hysteroskopie.

OBJECTIVE: Sum up the knowledge about office hysteroscopy. TYPE OF STUDY: Review of literature and our own 5 years of experience. SETTING: Department of Gynaecology and Obstetrics, First Faculty of Medicine, Charles University Prague and General Teaching Hospital Prague, Prague. METHODS: Compilation of data from scientific literature and 5 years of our own experience with office hysteroscopy. CONCLUSIONS: Hysteroscopy provides optical evaluation of uterine cavity. Most of the benign intrauterine organics pathologies could be managed in an outpatient setting with a vaginoscopic approach without any anaesthesia and analgesia. Using that approach we can recommend to perform endometrial target biopsy, resection of endometrial polyps up to 1.5 cm and pedunculated submucous myomas up to 1 cm as well as resection of filmy intrauterine adhesions. Method is comfortable for well managed patients and practically complication-free.

["See and treat" hysteroscopy: limits of intrauterine pathology bulk]. / "See and treat" hysteroskopie: limity velikosti intrauterinní patologie.

OBJECTIVE: To evaluate bulk limits of intrauterine pathology for "see and treat" hysteroscopy. TYPE OF STUDY: A retrospective observational study. SETTING: Department of Gynaecology and Obstetrics, First Faculty of Medicine, Charles University Prague and General Teaching Hospital Prague. METHODS: 200 mg of Indomethacin was administered to the patients by rectum 2 hours before procedure. "See and treat" procedures were performed with "Versascope" in awake patients without any peroperatively admistered analgesia or anaesthesia. As a "see and treat" were managed 796 endometrial polyps, 125 submucous myomas, as well as 62 cases of intrauterine synechias. CONCLUSIONS: endometrial polyps up to 1,5 cm, pedunculated submucous myomas up to 1,0 cm as well as fibroid adhesiones obliterated no more than 1/3 of uterine cavity can be managed as "see and treat" procedures with a high compliance of the patients.

Skin and diabetes.

Skin manifestations associated with diabetes mellitus are common and, with close scrutiny, can occur in most, if not all, patients. Little information is available on what common pathophysiologic thread is responsible for the skin manifestation and diabetes. Although controlled studies are lacking, a recognition of the skin manifestations, treatment, and prognosis will help patients and their caregivers to understand treatment alternatives more clearly.

Proliferating cell nuclear antigen (PCNA); prognostic value in the clinical recurrence of primary basal cell carcinoma.

Proliferating cell nuclear antigen (PCNA) is a nuclear protein which is correlated with the S-phase of the cell cycle and has been utilized by many investigators as a marker of cell proliferation. A previous immunohistochemical study revealed increased PCNA staining in clinically and histologically aggressive basal cell carcinoma and the present study evaluated the prognostic value of PCNA in clinical recurrence of primary basal cell carcinoma. Thirty patients with primary basal cell carcinoma (BCC) treated with shave biopsy followed by electrodesiccation in 1989 and have been regularly followed up for local recurrence were selected for this study. The histology of their primary BCC's was reviewed and the presence of PCNA in the tumor cells was studied immunohistochemically. Ninety-six percent of the non-recurrent BCC's had < 10% of tumor cells showing a positive staining for PCNA whereas 100% of the BCC's that recurred showed more than 30% of tumor cells staining positive for PCNA. In comparison, 88.9% of the non-recurring group showed non-aggressive histological features and only 66.7% of the recurring group was aggressive by microscopic appearance. In summary, the PCNA staining appeared to be superior to traditional histologic features in predicting clinical recurrence in primary BCC's and further prospective studies in a larger patient group are warranted.

Protein expression in the stressed Vibrio strains.

In a conjunction process using Escherichia coli SM10 (pLOF) KmR APR as donor and Vibrio S141 SmR as recipient, several mutants were constructed: Vibrio PH 101, V. PH 106, and V. PH 109 with lowered ability to synthesize poly-beta-hydroxybutyrate. The survival and metabolic activities of parent and mutant strains were estimated when they were subjected to stress conditions (starvation of carbon and energy sources and/or cadmium treatment). Using two-dimensional electrophoresis, the synthesis of stress proteins was demonstrated. Vibrio cultures consecutively exposed to CdCl2 and then to starvation or vice versa responded similarly metabolically. These results show increased proteosynthetic activity of the stressed Vibrio cells, indicating that the primary cadmium treatment induced the expression and synthesis of the protective proteins, enabling the cells to cope with the secondary stress.

Effects of ammonium and lactate on growth and metabolism of a recombinant Chinese hamster ovary cell culture.

A Chinese hamster ovary (CHO) cell line producing a recombinant glycoprotein was cultured in batch mode with different initial concentrations of ammonium chloride (0-10 mM), sodium lactate (0-60 mM), or sodium chloride (0-60 mM). High ammonium concentrations did not inhibit cell growth and productivity or glucose and glutamine consumption. In contrast, specific ammonia and alanine production decreased by 55% and 40%, respectively. There were also significant increases in specific aspartate and glutamate consumption in high ammonium concentrations. These observations indicated a shift in glutamine catabolic pathways in response to the effects of ammonium. The influence of lactate on growth and metabolism were the combined effects of lactate concentration and osmolarity. After "correcting" for osmolarity effects, lactate was found to inhibit growth by 25% but to increase specific productivity slightly (10%). Lactate had profound effects not only on glycolysis but also on glutaminolysis. While specific glucose and glutamine consumptions decreased by 15-20%, the effects of lactate on their metabolic products were far more significant. Lactate production was halted, and specific ammonia and alanine productions decreased by 64% and 70% at high lactate concentration. Theories on how ammonium and lactate affected the metabolic pathways of glucose and glutamine are presented.

Human cerebral perfusion analysis with ultrasound contrast agent constant infusion: a pilot study on healthy volunteers.

With ultrasound (US) contrast agent (UCA) continuous infusion providing a steady state, mean tissue microbubble velocity can be assessed by analyzing the reappearance rate after microbubble destruction with US energy (refill kinetics). In this study, we investigated this new approach for the assessment of human cerebral perfusion. A total of 12 healthy volunteers were investigated transtemporally with increasing pulsing intervals (250, 500, 750, 1000, 1250, 1500, 2000, 3000 and 4000 ms) and two UCA infusion rates (0.5 and 1.0 mL/min of Optison). Intensity vs. pulsing interval curves were analyzed using an exponential curve fit and parameters of the curve (plateau echo enhancement, A, representing the microbubble concentration within the interrogated tissue; rate constant, beta, which is related to blood flow and their product, F = Abeta) were compared. For 20/20 investigations being available for further analysis, it was possible to generate a typical exponential intensity vs. pulsing interval curve from the ipsilateral thalamus. The plateau echo enhancement A showed a significant (p = 0.02), and the beta as well as the F values displayed a nonsignificant (p = 0.06, both), increase with infusion rate. The qualitative analysis of beta and F parameter images displayed the most homogeneous visualisation of perfusion in the ipsilateral thalamus and main territory of the middle cerebral artery. In conclusion, it is possible to display the UCA refill kinetics in human cerebral microcirculation after microbubble destruction by transcranial US. Grey-scale harmonic imaging allows a quantitative approach to cerebral perfusion with a large interindividual variation of the parameters.