Unravelling Receptor and RGD Motif Dependence of Retargeted Adenoviral Vectors using Advanced Tumor Model Systems.

Recent advances in engineering adenoviruses are paving the way for new therapeutic gene delivery approaches in cancer. However, there is limited knowledge regarding the impact of adenoviral retargeting on transduction efficiency in more complex tumor architectures, and the role of the RGD loop at the penton base in retargeting is unclear. To address this gap, we used tumor models of increasing complexity to study the role of the receptor and the RGD motif. Employing tumor-fibroblast co-culture models, we demonstrate the importance of the RGD motif for efficient transduction in 2D through the epithelial cell adhesion molecule (EpCAM), but not the epidermal growth factor receptor (EGFR). Via optical clearing of co-culture spheroids, we show that the RGD motif is required for transduction via both receptors in 3D tumor architectures. We subsequently employed a custom-designed microfluidic model containing collagen-embedded tumor spheroids, mimicking the interplay between interstitial flow, extracellular matrix and adenoviral transduction. Image analysis of on-chip cleared spheroids indicated the importance of the RGD motif for on-chip adenoviral transduction. Together, our results show the interrelationship between receptor characteristics, the RGD motif, the 3D tumor architecture and retargeted adenoviral transduction efficiency. The findings are important for the rational design of next-generation therapeutic adenoviruses.

DNA-functionalized hydrogels for confined membrane-free in vitro transcription/translation.

We microfluidically fabricate bio-orthogonal DNA-functionalized porous hydrogels from hyaluronic acid that are employed in in vitro transcription/translation (IVTT) of a green fluorescent protein. By co-encapsulating individual hydrogel particles and the IVTT machinery in water-in-oil microdroplets, we study protein expression in a defined reaction volume. Our approach enables precise control over protein expression rates by gene dosage. We show that gene transcription and translation are confined to the membrane-free hydrogel matrix, which contributes to the design of membrane-free protocells.

Artificial microniches for probing mesenchymal stem cell fate in 3D.

Droplet microfluidics is combined with bio-orthogonal thiol-ene click chemistry to fabricate micrometer-sized, monodisperse fibrinogen-containing hyaluronic acid hydrogel microbeads in a mild, radical-free procedure in the presence of human mesenchymal stem cells (hMSCs). The gel beads serve as microniches for the 3D culture of single hMSCs, containing hyaluronic acid and additional fibrinogen for cell surface binding, and they are porous and stable in tissue culture medium for up to 4 weeks with mechanical properties right in the range of soft solid tissues (0.9-9.2 kPa). The encapsulation procedure results in 70% viable hMSCs in the microbeads after 24 hours of culture and a very high degree of viability of the cells after long term culture of 2 weeks. hMSCs embedded in the microniches display an overall rounded morphology, consistent with those previously observed in 3D culture. Upon induction, the multipotency and differentiation potential of the hMSCs are characterized by staining of corresponding biomarkers, demonstrating a clear heterogeneity in the cell population. These hydrogel microbeads represent a versatile microstructured material platform with great potential for studying the differences of material cues and soluble factors in stem cell differentiation in a 3D tissue-like environment at the single cell level.

Tratamiento del pezón invertido: comparación de dos técnicas / Treatment of the inverted nipple: comparisson of two different techniques

El objeto del trabajo es presentar los resultados comparativos de 2 técnicas elegidas por los autores para el tratamiento del pezón invertido. La elección de los procedimientos está en relación a su simplicidad y corta curva de aprendizaje. Se analizan los resultados de las 2 técnicas, indicaciones, complicaciones y resultados a largo plazo (AU)

The aim of this paper is to present the results of 2 different techniques chosen by the authors for the treatment of inverted nipples. The selection of the procedures is in relation of the simplicity and the short learning curve. We analyzed the results of the 2 techniques, indications, complications and long-term results (AU)

Dewetting of conducting polymer inkjet droplets on patterned surfaces.

The manufacture of high-performance electronic devices with micrometre or even submicrometre dimensions by solution processing and direct printing, requires the ability to control accurately the flow and spread of functional liquid inks on surfaces. This can be achieved with the help of surface-energy patterns causing inks to be repelled and dewetted from pre-defined regions of the substrate. To exploit this principle for the fabrication of submicrometre device structures, a detailed understanding of the factors causing ink droplets to dewet on patterned surfaces is required. Here, we use hydrophobic surface-energy barriers of different geometries to study the influence of solution viscosity, ink volume, and contact angle on the process of dewetting of inkjet-printed droplets of a water-based conducting polymer. We demonstrate polymer field-effect transistor devices with channel length of 500 nm fabricated by surface-energy-assisted inkjet printing.

Patterning electro-osmotic flow with patterned surface charge.

This Letter reports the measurement of electro-osmotic flows (EOF) in microchannels with surface charge patterned on the 200 microm scale. We have investigated two classes of patterns: (1) Those in which the surface charge varies along a direction perpendicular to the electric field used to drive the EOF; this type of pattern generates multidirectional flow along the direction of the field. (2) Those in which the surface charge pattern varies parallel to the field; this pattern generates recirculating cellular flow, and thus causes motion both parallel and perpendicular to the external field. Measurements of both of these flows agree well with theory in the limit of thin double layers and low surface potential.

Comparison of moxifloxacin and cefuroxime axetil in the treatment of acute maxillary sinusitis. Sinusitis Infection Study Group.

The aim of this prospective, multicenter, randomized, double-masked clinical trial was to compare the efficacy and safety of moxifloxacin with those of cefuroxime axetil for the treatment of community-acquired acute sinusitis. Five hundred forty-two adult patients with symptoms and radiographic evidence of acute maxillary sinusitis received a 10-day oral regimen of either moxifloxacin (400 mg once daily) or cefuroxime axetil (250 mg twice daily). Acute signs and symptoms at presentation had lasted >7 days but <4 weeks. Clinical response at the end of therapy (7 to 14 days after treatment) was the primary efficacy variable. Four hundred fifty-seven of the patients (223 moxifloxacin, 234 cefuroxime axetil) were included in the clinical efficacy analysis. Moxifloxacin was found to be similar in effectiveness to cefuroxime axetil at the end-of-therapy visit (90% vs. 89%, respectively; 95% confidence interval, -5.1% to 6.2%). Clinical relapse at the follow-up visit was reported for only 8 patients (3 moxifloxacin, 5 cefuroxime axetil). No clinically significant differences were observed with respect to the number of patients experiencing a successful clinical response based on demographic or infection characteristics. Five of the 542 enrolled patients were lost to follow-up. Of the 537 patients in the intent-to-treat population, drug-related adverse events were reported in 37% of moxifloxacin-treated patients and in 26% of cefuroxime axetil-treated patients (P = 0.006). Adverse-event profiles were comparable in the 2 treatment groups, with the exception of nausea, which was reported by 11% of moxifloxacin-treated patients compared with 4% of cef uroxime axetil-treated patients (P = 0.003). In this study, moxifloxacin was as effective as cefuroxime axetil in the treatment of community-acquired acute sinusitis.

Double-blind comparative trial of ciprofloxacin versus clarithromycin in the treatment of acute bacterial sinusitis. Sinusitis Infection Study Group.

This multicenter, randomized, double-blind trial compared the efficacy and safety of ciprofloxacin (CIP; 500 mg twice daily for 10 days, placebo for 4 days) to those of clarithromycin (CLARI; 500 mg twice daily for 14 days) in 560 adults with clinically documented and radiologically confirmed acute sinusitis. Of 457 efficacy-valid adults (236 CIP, 221 CLARI), clinical resolution plus improvement at the end of therapy was 84% for CIP-treated patients compared to 91% of CLARI recipients (CI95 = -0.131, -0.013). At the 1-month follow-up, more than twice as many CLARI-treated patients, 18 (10%), experienced a relapse, compared to 7 (4%) CIP-treated patients. The combined clinical response analyses (end of therapy and 1 -month follow-up) demonstrated that CIP and CLARI were statistically equivalent (CI95 = -0.106, 0.044). Diarrhea, nausea, headache, and dizziness were the most frequently reported drug-related adverse events in both treatment groups; diarrhea and taste perversion were reported more frequently among CLARI recipients. In summary, the combined end of therapy and follow-up clinical evaluation analyses revealed that CIP and CLARI were equally effective in the management of acute sinusitis, although twice as many relapses were reported among CLARI recipients.

A randomized trial of short-course ciprofloxacin, ofloxacin, or trimethoprim/sulfamethoxazole for the treatment of acute urinary tract infection in women. Ciprofloxacin Urinary Tract Infection Group.

PURPOSE: Bladder infections are very common in otherwise healthy women, and short-course antimicrobial treatment appears effective for many episodes of cystitis. This study reports the results of short-course ciprofloxacin, ofloxacin, and trimethoprim/sulfamethoxazole therapy. PATIENTS AND METHODS: We performed a randomized, double-blind study of the efficacy and safety of a 3-day course of oral ciprofloxacin 100 mg twice daily, ofloxacin 200 mg twice daily, or trimethoprim/sulfamethoxazole 160/800 mg twice daily in women with acute, uncomplicated, symptomatic lower urinary tract infection. RESULTS: A total of 866 patients were enrolled, of whom 688 (79%) were evaluated for the efficacy of treatment (229 treated with ciprofloxacin, 228 treated with trimethoprim/sulfamethoxazole, and 231 treated with ofloxacin). The most frequent reason for exclusion was the failure to identify a pretreatment pathogen. The most commonly isolated pathogen was Escherichia coli (81%). Eradication of the pretreatment pathogen at the end of therapy occurred in 94% of ciprofloxacin, 93% of trimethoprim/sulfamethoxazole, and 97% of ofloxacin-treated patients. At follow-up evaluation at 4 to 6 weeks, recurrence rates (relapse or reinfection) were 11% in the ciprofloxacin, 16% in the trimethoprim/sulfamethoxazole, and 13% in the ofloxacin treatment group. Clinical success at the end of therapy was 93% in the ciprofloxacin, 95% in the trimethoprim/sulfamethoxazole, and 96% in the ofloxacin treatment groups. The frequency of all adverse events was 31% for ciprofloxacin, 41% for trimethoprim/sulfamethoxazole, and 39% for ofloxacin-treated patients (P = 0.03). Premature discontinuation of study drug due to an adverse event was more common in trimethoprim/sulfamethoxazole-treated patients (n = 9) compared with those given ciprofloxacin (n = 2) or ofloxacin (n = 1; P = 0.02). CONCLUSION: Ciprofloxacin, ofloxacin, and trimethoprim/sulfamethoxazole had similar efficacy when given for 3 days to treat acute, symptomatic, uncomplicated lower urinary tract infection in women.

Ciprofloxacin versus cefuroxime axetil in the treatment of acute bacterial sinusitis. Sinusitis Infection Study Group.

OBJECTIVE: This study was conducted to compare the efficacy and safety of ciprofloxacin to cefuroxime axetil for the management of acute bacterial sinusitis or acute exacerbations of chronic sinusitis. METHOD: In this prospective, multicentre, randomized, double-blind clinical trial, 501 adult outpatients seen in 17 otolaryngology offices with both symptoms and radiographic evidence of acute maxillary sinusitis randomly received oral ciprofloxacin (500 mg b.i.d.) or cefuroxime axetil (250 mg b.i.d.), each for 10 days. Patients were further subclassified as having either acute sinusitis or an acute exacerbation of chronic sinusitis. All patients underwent maxillary sinus aspiration at study entry to establish a microbiologic etiology. The primary measure of efficacy was the rate of clinical success in the efficacy-valid population at the end of therapy. Secondary measures included bacteriologic response at the end of therapy, and 2- to 4-week clinical and bacteriologic follow-up response rates in both efficacy-valid and intent-to-treat groups. RESULTS: Haemophilus influenzae (21%), Streptococcus pneumoniae (19%), Moraxella catarrhalis (14%), and Staphylococcus aureus (9%) were the most commonly isolated pathogens (target organisms) among the 225 causative organisms identified from 189 patients. Of 453 adults valid for clinical efficacy (228 ciprofloxacin, 225 cefuroxime axetil), ciprofloxacin treatment was statistically equivalent to cefuroxime axetil at the end of treatment (87% vs. 83%; CI95 = -0.021 ... 0.106) and at follow-up (91% vs. 88%; CI95 = -0.044 ... 0.080). The clinical response was similar for subgroups of patients with positive cultures, including the subset with target organisms. Bacteriologic eradication at end of therapy was similar between the two groups (97% ciprofloxacin, 95% cefuroxime axetil). Both treatments were equally well tolerated. CONCLUSION: Ciprofloxacin is as effective as cefuroxime axetil in the treatment of community-acquired acute sinusitis.

Comparison of dirithromycin and penicillin for treatment of streptococcal pharyngitis.

In the treatment of group A beta-hemolytic streptococcal pharyngitis, penicillin is the drug of choice and erythromycin is the alternative. In a double-blind, randomized study, dirithromycin, a new macrolide, was compared with penicillin for the treatment of streptococcal pharyngitis. Of 121 patients who were treated with dirithromycin, 96.7% manifested a favorable clinical response, and of 136 patients treated with penicillin, 94.2% manifested a favorable clinical response. Streptococci were eradicated from the pharynges of 85.3% of 116 dirithromycin-treated patients and 82.5% of 126 penicillin-treated patients who returned for follow-up. There were no statistically significant differences in efficacy between the two groups. The incidence of abdominal symptoms was higher in dirithromycin-treated patients. Being as efficacious as penicillin and having the advantages over erythromycin of once-daily dosing and the lack of drug interactions, dirithromycin is an alternative to penicillin in the treatment of streptococcal pharyngitis for patients 12 years of age and older.

Cefaclor vs amoxicillin in the treatment of acute, recurrent, and chronic sinusitis.

BACKGROUND: The treatment of acute, recurrent, and chronic sinusitis remains controversial because of the presence of a wide variety of aerobic and anaerobic bacteria in the sinuses. DESIGN: This double-blind, randomized trial compared cefaclor with amoxicillin in the treatment of acute, recurrent, and chronic maxillary sinusitis using clinical evaluation, roentgenography, and microbiologic evaluation of antral aspirates. SETTING: Outpatient office of five otorhinolaryngologists in Salt Lake City, Utah. PATIENTS: One hundred eight adult patients with acute, recurrent, or chronic maxillary sinusitis. INTERVENTION: Oral treatment with cefaclor (500 mg) twice daily or amoxicillin (500 mg) three times daily for 10 days. MAIN OUTCOME MEASURE: Clinical response to treatment with cefaclor vs amoxicillin. RESULTS: Fifty-six patients with acute sinusitis, 25 with recurrent sinusitis, and 15 with chronic sinusitis were evaluable. Although multiple organisms were common in each group, patients with acute sinusitis were more likely to have Haemophilus influenzae or Streptococcus pneumoniae, and patients with recurrent or chronic sinusitis were more likely to have anaerobes in sinus aspirate. Whether treated with cefaclor or amoxicillin, clinical improvement occurred in 86% of patients with acute sinusitis and 56% of patients with recurrent sinusitis. Patients with chronic sinusitis were too few to allow statistical analysis of the differences in outcome between them and patients with recurrent or acute sinusitis. Resistance of the cultured organisms to the study drug used was unrelated to treatment outcome. CONCLUSIONS: The rate of clinical improvement was high in patients with acute sinusitis but was less favorable in those with recurrent and chronic disease regardless of the study drug used. The susceptibility of organisms isolated to the study drugs was unrelated to outcome.

Loracarbef (LY 163892) vs amoxicillin/clavulanate in bacterial maxillary sinusitis.

Loracarbef (LY 163892), a beta-lactam antibiotic (carbacephem), was compared with amoxicillin/clavulanate potassium in a 10-day, single-blind, randomized parallel trial in the treatment of acute bacterial maxillary sinusitis. Based on posttherapy aspirate and culture, there was a 95.2% bacteriologic cure rate in patients receiving loracarbef (400 mg twice daily) and an 86.7% cure rate in patients receiving amoxicillin/clavulanate (500/125 mg three times daily) (p = 0.359). Loracarbef was comparable in efficacy to amoxicillin/clavulanate with a more desirable safety profile.

Treatment of beta-hemolytic streptococcal pharyngitis with cefaclor or penicillin. Efficacy and interaction with beta-lactamase-producing organisms in the pharynx.

The recommended treatment for group A beta-hemolytic streptococcal pharyngitis has continued to be penicillin given in parenteral or oral form. Treatment failures, as determined by the continued presence of the streptococcal organism in the pharynx, however, do occur in 6% to 25% of patients treated with penicillin. Furthermore, beta-lactamase produced by other bacteria in the pharynx could potentially inactivate the penicillin, resulting in increased treatment failures or infection relapses. A study was undertaken to compare the efficacy of cefaclor, which is relatively resistant to inactivation by beta-lactamase, with penicillin for eradicating the group A beta-hemolytic streptococcal organism from the throats of 93 patients with pharyngitis. Additionally, extensive cultures for potential beta-lactamase-producing organisms were conducted on 37 patients; 27% of these had one or more pharyngeal organisms that were producing beta-lactamase. No statistically significant difference was found between the clinical responses or the bacteriological cure rates of those treated with cefaclor and those treated with penicillin when stratified by the presence or absence of beta-lactamase-producing organisms. The prevalence of beta-lactamase-producing organisms in the pharynx, however, was increased after treatment with penicillin, whereas no change was noted following treatment with cefaclor.

Diagnosis of group A beta-hemolytic Streptococcus using clinical scoring criteria, Directigen 1-2-3 group A streptococcal test, and culture.

Cultures for group A beta-hemolytic Streptococcus were performed on 806 patients presenting with a sore throat to five urgent care centers. The accuracies of a clinical scoring system and of a liposomal in-office direct test for Streptococcus were compared with culture results. The Directigen 1-2-3 group A streptococcal test had a sensitivity of 67%, a specificity of 85%, a positive predictive value of 61%, and a negative predictive value of 89% compared with culture. The scoring system had a sensitivity of 26%, a specificity of 94%, a positive predictive value of 58%, and a negative predictive value of 79%. Using a combination of the direct test results and the clinical score did not improve the accuracy significantly over the use of either alone. The rates of delayed treatment, unnecessary treatment, and increased costs were compared using different combinations of the clinical scoring system, the in-office streptococcal test, and culture. Neither the Directigen 1-2-3 group A streptococcal test nor the clinical score can replace culture in the diagnosis of group A beta-hemolytic streptococcal pharyngitis.

[Replay and reproduction of the national socialism past in psychotherapy of adolescent patients]. / Wiederspiel und Abbild der nationalsozialistischen Vergangenheit in der Psychotherapie jugendlicher Patienten.

This study explores the repetition of specific Nazipatterns in the family therapy of drug addicted adolescents. It is shown that 40 years after World War II the tragic events are still repressed. This study aims at a closer connection of psychotherapy and a model built up from social and historical perspectives.

The integration of patients with a drug-induced psychosis into a clientele of polytoxicomanic patients.

Over the last years a clear increase in serious psychic disorders and particulary in the area of drugs an increase of patients with a drug-induced psychosis can be established. In this contribution experiences we made over the last four years in the attempt at integrating patients with drug-induced psychosis into a clientele of polytoxicomanic patients are presented. Here, particulary from the systemic point of view, the rules and patterns of the families are presented because these rules and patterns are newly staged in the in-patient setting. The detachment and the development of a life of one's own responsibility is seen as the main problem of the patients with a drug-induced psychosis. Experiences up until now show that an integration of this clientele is successful even if the therapeutical process poses many difficulties for the fellow-patients and the team.

Comparison of the Directigen 1-2-3 Group A Strep Test with culture for detection of group A beta-hemolytic streptococci.

The Directigen 1-2-3 Group A Strep Test (DGAST; BBL Microbiology Systems, Cockeysville, Md.) was compared with conventional culture procedures on Trypticase soy agar with 5% sheep blood (BBL) and Selective Streptococcal Agar (ssA; BBL) for detection of group A beta-hemolytic streptococci (GABHS) for 1,006 patients complaining of sore throat. The DGAST was performed at five acute-care clinics according to the instructions of the manufacturer; interpretation of the cultures was done at the central microbiology laboratory. Of 924 patients with complete data, 243 (26.3%) were positive for GABHS on culture when both sheep blood agar and ssA were used. Of the patients with positive cultures, 159 were detected by the DGAST, yielding a sensitivity of 65.4%, a specificity of 84.7%, a positive predictive value of 60.5%, and a negative predictive value of 87.3%. The greater the number of colonies on culture, the greater the sensitivity of the DGAST, and the more intense the positive reaction on the DGAST, the higher the positive predictive value of the test. For the identification of GABHS, sheep blood agar was superior to ssA by 12.9% at 24 h and by 3.4% at 48 h of incubation.

Differentiation of Gardnerella vaginalis, Candida albicans, and Trichomonas vaginalis infections of the vagina.

This study evaluated the positive predictive values of factors associated with Gardnerella vaginalis, Candida albicans, and Trichomonas vaginalis for diagnosing vaginitis in a community-based population. One hundred ninety-six women with and without vaginal complaints were evaluated for historical factors, physical examination findings, and office laboratory results that were potentially associated with each of the three vaginal organisms. Extensive microbiological tests were performed to detect pathogenic organisms in the vagina and cervix. Gardnerella vaginalis was associated with findings of clue cells, gray or creamy vaginal discharge, amine ordor on application of potassium hydroxide solution to the discharge, pH greater than 5, and a history of more than six sexual partners. Candida albicans was associated with the presence of pseudohyphae or budding yeast on microscopic examination and the lack of clue cells. Current use of oral contraceptives and the recent use of antibiotics were not predictive of a Candida albicans infection. Trichomonas vaginalis was more common in patients presenting with symptoms, but otherwise was not predicted by the factors tested.