Structured drug-eluting bioresorbable films: microstructure and release profile.

Bioresorbable drug-eluting films can be used in many biomedical applications. Examples for such applications include biodegradable medical support devices which combine mechanical support with drug release and antibiotic-eluting film coatings for prevention of bacterial infections associated with orthopedic implants or during gingival healing. In the current study, bioresorbable drug-loaded polymer films are prepared by solution processing. Two film structures are studied: A polymer film with large drug crystals located on its surface (A-type) and a polymer film with small drug particles and crystals distributed within the bulk (B-type). The basic mode of drug dispersion/location in the film (A or B-type) is found to be determined mainly by the process of film formation and depends mainly on the solvent evaporation rate, whereas the drug's hydrophilicity has a minor effect on this structuring process. Most release profiles from A-type films exhibit a burst effect of approximately 30% and a second release stage that occurs at an approximately constant rate and is determined mainly by the polymer weight loss rate. An extremely high burst release is exhibited only by a very hydrophilic drug. The matrix (monolithic) nature of the B-type film enables release profiles that are determined mainly by the host polymer's degradation profile, with a very low burst effect in most of the studied systems. In addition to the drug location/ dispersion in the film, the host polymer and drug type also strongly affect the drug's release profile from the film. It has been demonstrated that appropriate selection of the process parameters and film components (polymer and drug) can yield film structures with desirable drug release behaviors. This can lead to the engineering of new bioresorbable drug-eluting film-based implants for various applications.

Molecular and cellular characterization of mesenchymal progenitors for skeletal biomedical devices.

Mesenchymal cells are successfully used to create cell-loaded devices in tissue engineering. Molecular properties of the cells and interaction with polymer scaffolds regulate the development of desired tissues. The present study compared the molecular markers in mesenchymal pleuripotent C3H10T1/2 and osteogenic MBA-15 cells. The cells express transcription factors (TF) of chondro-ostegenic pathway (cbfa-1 and c-fos) and MyoD - TF of muscle differentiation pathway, but not myogenin. Analyzed cells expressed receptors for glucocorticoids, growth hormone, prolactin, and PTH, which indicates their potential responsiveness to systemic signals. Analysis of mRNA encoding for receptors of TGFbeta, TNF, and various interleukins revealed differential expression of IL-2r and TGFbeta-1r receptors, which were expressed by MBA-15 but not by C3H10T1/2 cells. Expression of functional genes indicates differences in the stages of cell differentiation: ALK was present in MBA-15 only, while both cell types expressed collagen-I. Furthermore, we evaluated the expression of adhesion proteins that mediate cell-polymer interactions by flow cytometry analysis. Cell adhesion molecules (CAMs) analyzed were integrinalpha-M (CD11b), selectin-E (CD62E), and PECAM-1 (CD31), which have shown differential expression on cells cultured on plastic, poly(L-lactic acid) (PLLA) or poly(DL-lactide-glycolide acid) (PDLGA) polymer films. Detailed molecular characterization of mesenchymal cells will enable optimization of culture conditions for successful creation of implantable cell-loaded constructs.

Congenital hepatic arteriovenous malformation: an unusual cause of neonatal persistent pulmonary hypertension.

Congenital hepatic arteriovenous malformations are rare anomalies, which typically present in infancy with congestive heart failure, anemia, and hepatomegaly. Morbidity and mortality is high if the condition is not recognized and treated promptly. Hepatic arteriovenous malformation associated with persistent pulmonary hypertension of the newborn has been reported in two cases in the literature. We report a neonate who was referred for management of persistent pulmonary hypertension and was subsequently diagnosed with a large hepatic arteriovenous malformation. He underwent coil embolization following which pulmonary hypertension resolved.

Adhesion molecule expression by osteogenic cells cultured on various biodegradable scaffolds.

Design of tissue-engineered cell-loaded device involves cells seeding onto scaffolds in vitro, allowing them to settle and grow before in vivo transplantation. Interaction between scaffold and cells is important in the development of desired tissues. The present study aimed to investigate the effect of cell-polymer interactions on cell morphology and expression of surface markers of osteogenic MBA-15 cells cultured on various bioresorbable polymers. In this study, we used various polymers: poly(L-lactic acid) (PLLA), poly(DL-lactic acid) (PDLLA), poly(L-lactic-glycolic acid) (PLGA), and poly(DL-lactide-glycolide acid) PDLGA1 and PDLGA2. Expression of integrinalpha-M (CD11b), selectin-E (CD62E), and PECAM-1 (CD31), important in cell-cell and cell-matrix interactions, were quantified by flow-cytometry analysis. Cells grown on PDLGA1 films demonstrated fivefold increase in CD62E expression and two-folds increase in CD11b expression. None of the polymers affected the levels of CD31. Identified differential effect of polymers on the expression of cell-adhesion molecules by osteoprogenitors in vitro might help to choose optimal parameters for successful engraftment of cell-loaded constructs.

Dexamethasone loaded bioresorbable films used in medical support devices: structure, degradation, crystallinity and drug release.

Bioresorbable polymer films containing dexamethasone (DM) were prepared using a solution processing technique. Investigation of the films focused on cumulative DM release as affected by film morphology (drug location/dispersion in the film) and degradation processes. Two film structures were studied: A-type, a polymer film with large drug crystals located on the film's surface, and B-type, a polymer film with small drug particles and crystals distributed within the bulk. The effect of the polymer's degree of crystallinity on the drug release profile was also studied. Prototypical applications of these films are biodegradable medical support devices which combine mechanical support with drug release. In most of our studied systems the drug release profile from the film is determined mainly by both drug location/dispersion in the film and the polymer's weight loss rate. All release profiles from A-type films exhibited a burst effect of approximately 30%, accompanied by a second release phase at a constant rate, whereas the release profiles from B-type films were determined mainly by the degradation profile of the host polymer, and did not exhibit any burst effect. A high degree of crystallinity is important for the current application, since good mechanical properties are required. This contributes to slower drug release rates, mainly at relatively low weight losses, whereas at high weight losses, where a porous structure is created, the crystallinity almost does not affect the rate of drug release. The shape of the porous structure that develops with degradation also affects the drug release profile from the B-type films.

Role of intestinal brush border membrane aminopeptidase N in dipeptide transport.

The kinetics of uptake of radioactive label from [U-14C]Gly, L-[4,5-3H]Leu and the dipeptide [14C]Gly-L-[4,5-3H]Leu by the brush border membrane vesicles of porcine small intestine have been studied. The effect of aminopeptidase N inhibitors and leucine-binding protein on accumulation rates has also been tested. Comparison of the kinetic parameters for uptake and hydrolysis of Gly-L-Leu makes it possible to conclude that the dipeptide transfer includes two conjugated steps, viz., hydrolysis catalysed by aminopeptidase N and transport of the resultant free amino acids by a specific carrier.

Evaluation and treatment of iatrogenic ureteral injuries during obstetric and gynecologic operations for nonmalignant conditions.

Twenty-one iatrogenic ureteral injuries (20 patients) as a result of obstetric and gynecologic operations are presented. All injuries occurred during operations for benign conditions, such as Cesarean section and transabdominal hysterectomy. Pelvic adhesions as a result of repeat Cesarean section, markedly enlarging the uterus at the time of abdominal hysterectomy, and massive hemorrhage during surgical treatment were the main causes of ureteral injury. Nine ureters were transected (eight patients) and 12 ureters had postoperative obstruction. Fistulas occurred between the affected ureter and the vagina (five patients), uterus (one patient) and skin (one patient). The existence and the site of such a fistula is clearly demonstrated roentgenographically using intravenous urograms while a urethral catheter filled with contrast media is inserted into the bladder. Only a few ureteric injuries (two patients) were diagnosed and managed during the initial gynecologic operation. The remainder underwent delayed repair procedures. In most patients, the upper urinary tract was protected by percutaneous nephrostomy. The preferred operation for definitive correction was ureteroneocystostomy using the psoas hitch procedure. Direct localization by difficult dissection of the injured ureteral site was unnecessary with ureteroneocystostomy because this procedure bypasses the site of the injury to the ureter. This procedure can be applied in most injuries to the ureter, distal or proximal, which occur during gynecologic and obstetric operations. Renal salvage was achieved in all instances, with no operative or postoperative complications.

[Tension-free vaginal tape--a new surgical treatment of female urinary stress incontinence].

Female urinary stress incontinence diminishes the quality of life of about 5% of women. It is usually dealt with by surgery to correct the relaxed pelvic floor, the cause of the incontinence. Tension-free vaginal tape is used in a newly described procedure. It consists of the vaginal introduction of a prolene needle-guided mid-urethral sling. The procedure is easy to perform under local anesthesia, recovery is rapid, and results are similar to those of other effective operations. We report 44 patients who underwent this type of surgery. There were no significant complications. The early results were good and although the follow-up has been short, we believe that experience with this operation will play an important role in the treatment of urinary stress incontinence.

[Multiple enteral fistulas in peritoneal tuberculosis].

A 40-year-old Ethiopian man had abdominal pain for a year and a half, diarrhea and weight loss. Multiple enteral fistulas were diagnosed by X-ray and colonoscopy. During investigation, the differential diagnosis was between Crohn's disease, intestinal lymphoma and intestinal tuberculosis. Therapeutic trial with corticosteroids was unsuccessful. At operation peritoneal tuberculosis was diagnosed and several entero-enteric fistulas were found, but there were no other intestinal lesions nor other foci of tuberculosis. Intestinal fistulas complicating peritoneal tuberculosis are rare in comparison with enteral tuberculosis, lymphoma or Crohn's disease. After the fistulas were closed surgically and antitubercular treatment given, the patient recovered, returned to his normal weight, and had no complaints.

The importance of the early detection of varicocele in adolescent males.

Varicocele is a common finding in adult and adolescent males and may lead to potential infertility. Many methods are available to the practitioner for evaluation of the problem. The least invasive is color duplex imaging of the spermatic vein, to visualize the presence of reflux (backflow) in the vein, as well as to define flow characteristics. It is recommended that adolescent males be screened using this modality beginning at age 10-15 years if they appear to have physical findings indicating a varicocele or if there is a family history of male fertility problems or varicocele. If a varicocele is found, then referral can be made for intervention if needed.

In vitro microbial inhibition and cellular response to novel biodegradable composite wound dressings with controlled release of antibiotics.

About 70% of all people with severe burns die from related infections, despite advances in treatment regimens and the best efforts of nurses and doctors. Although silver-eluting wound dressings are available for addressing this problem, there is growing evidence of the deleterious effects of such dressings in delaying the healing process owing to cellular toxicity. A new concept of antibiotic-eluting composite wound dressings is described here. These dressings are based on a polyglyconate mesh coated with a porous poly-(dl-lactic-co-glycolic acid) matrix loaded with antibiotic drugs. The effect of antibiotic release on bacterial inhibition was studied, and cell cytotoxicity was examined. The dressings resulted in a 99.99% decrease in the viable counts of Pseudomonas aeruginosa and Staphylococcus albus at very high initial inoculations of 107-108 CFU ml⁻¹ after only 1 day, while such a decrease in Staphylococcus aureus was obtained within 3 days. Bacterial inhibition zones around the dressing material were found to persist for 2 weeks, indicating a long-lasting antimicrobial effect. Despite severe toxicity to bacteria, the dressing material was found to have no toxic effect on cultured fibroblasts, indicating that the new antibiotic-eluting wound dressings represent an effective option for selective treatment of bacterial infections.

Restless legs syndrome (RLS) in anemic patients with congestive heart failure and chronic renal failure: lack of effect of anemia treatment.

OBJECTIVE: To assess the prevalence of Restless Legs Syndrome (RLS) in anemic patients with Congestive Heart Failure (CHF) and Chronic Renal Failure (CRF) and to evaluate the effect of anemia treatment on RLS. METHODS: 38 anemic CHF-CRF patients were treated with subcutaneous Erythropoietin (EPO) and intravenous (IV) iron over 1 year. They were questioned initially and at 3 months post treatment about symptoms of RLS according to standard criteria. They were also contacted by telephone about RLS symptoms 12 months after onset of anemia treatment. RESULTS: RLS was found in 15 (39.5%) of the 38 patients. In 10 (66.7%) patients it was present at least 6 days a week. The prevalence of the RLS initially was not related to Hb, to serum iron or % Transferrin Saturation. Diabetes and lower serum ferritin were more common in the RLS group (p<0.05). After 3 months of treatment, Hb increased from 10.4+/-0.8 to 12.3+/-1.2 g/dl, but RLS symptoms did not change. By 12 months the prevalence and frequency of RLS complaints was similar to what it had been initially. CONCLUSION: RLS is common and often undiagnosed and untreated in anemic CHF-CRF patients. Unfortunately, successful treatment of anemia with EPO and IV iron did not improve this condition.

Neural activity changes to emotional stimuli in healthy individuals under chronic use of clomipramine.

Previous functional magnetic resonance imaging (fMRI) studies examined neural activity responses to emotive stimuli in healthy individuals after acute/subacute administration of antidepressants. We now report the effects of repeated use of the antidepressant clomipramine on fMRI data acquired during presentation of emotion-provoking and neutral stimuli on healthy volunteers. A total of 12 volunteers were evaluated with fMRI after receiving low doses of clomipramine for 4 weeks and again after 4 weeks of washout. Fear-, happiness-, anger-provoking and neutral pictures from the International Affective Picture System (IAPS) were used. Data analysis was performed with statistical parametric mapping (P < 0.05). Paired t-test comparisons for each condition between medicated and unmedicated states showed, to negative valence paradigms, decrease in brain activity in the amygdala when participants were medicated. We also demonstrated, across both positive and negative valence paradigms, consistent decreases in brain activity in the medicated state in the anterior cingulate gyrus and insula. This is the first report of modulatory effects of repeated antidepressant use on the central representation of somatic states in response to emotions of both negative and positive valences in healthy individuals. Also, our results corroborate findings of antidepressant-induced temporolimbic activity changes to emotion-provoking stimuli obtained in studies of subjects treated acutely with such agents.

Two-dimensional echocardiographic valve measurements in healthy children: gender-specific differences.

The goal of this study was to create nomograms of echocardiographic two-dimensional valve dimensions based on a large group of children without heart disease. Children aged 0-18 years underwent standard echocardiographic evaluation. Referring diagnoses were chest pain, heart murmur, or syncope. Only patients with a structurally normal heart and normal systolic and diastolic function were included. All four valves were measured at their maximal dimensions. A total of 748 children (314 girls and 434 boys) met the inclusion criteria. Mean values and standard deviations were calculated, and z value nomograms based on body surface area were developed. Surprisingly, the boys had larger valve dimensions at all ages. These valve dimension differences were statistically significant for three of four valves even after adjustment for the differences in body sizes. The difference may be due to higher circulating blood volume in boys compared to that in girls. Because the differences are subtle, they reach statistical significance only when evaluated in a large group of subjects. Presented normal value data will be helpful in following cardiology patients and evaluating intervention strategy in patients with valve hypoplasia.

Bacteremia in anal dilatation.

One hundred patients underwent anal dilatation for acute or chronic anal fissure during the period 1983-1984; white blood count, serum, muscle enzymes, and blood cultures were done. Positive blood cultures were found following the procedure in eight patients. A correlation based on serum enzymes, bacteremia, and trauma can be made. Prophylactic broad-spectrum antibiotics are recommended for patients at risk.

Women alcoholics--social, demographic and clinical characteristics in a Brazilian sample.

We compared 115 female and 115 male Brazilian alcoholics in terms of their social and demographic characteristics, as well as other characteristics associated with alcohol consumption. Women both began drinking and increased their consumption later than men. The incidence of attempted suicide was higher among women. Females used less illicit drugs. Male alcoholics were more frequently born in the city of São Paulo. As for adherence to treatment in an out-patient clinic, no significant differences were found between the sexes 3, 6, 9 and 12 months after initiation of treatment.

Experience with the immediate treatment of iatrogenic bladder injuries and the repair of complex vesico-vaginal fistulae by the transvesical approach.

We describe our experience in treating 16 established cases of vesicovaginal fistulae in non-irradiated bladders which followed obstetric and gynecological procedures. The fistulae, most of which were large and complex, were successfully repaired surgically after two to three months intervals, using the O'Connor transvesical technique. The advantages of late correction using the transvesical approach in such cases are discussed. Thirteen additional cases of accidental bladder injuries during obstetric and gynecological procedures are presented. These injuries were successfully treated by immediate primary sutures. Our experience shows that bladder injuries mainly occur in women who had previously had a Cesarean section.

A comparative study of radioligand (DCC) and modified immunoperoxidase anti-estrogen receptor techniques in breast carcinoma.

This study deals with the pattern of estrogen receptors in 52 cases of invasive breast carcinoma by comparing the ligand-binding assays with dextran-coated charcoal (DCC) to an immunoperoxidase assay (IPE) technique in paraffin-embedded material from the same tumor. A modification of the IPE by adding cobalt chloride in the final reaction and counter-staining with eosin instead of hematoxylin was introduced. A significantly high correlation was found between the two compared methods (80.8% positivity by the DCC method and 80% by the IPE method). The correlation was very significant in cases where the immunohistochemical grading was higher than 4 (according to our semi-quantitative evaluation scale of 0-8), and for these cases we suggest the IPE method as highly specific and precise.

One-stage repair of hypospadias--experience with 856 cases.

OBJECTIVES: 856 cases of hypospadias, operated over a period of 7 years, using various methods of one-stage repair, are reviewed in order to assess their functional and cosmetic results and their rate of complications. PATIENTS AND METHODS: 856 boys with an average age of 3.5 years were classified according to the classification proposed by Duckett (anterior, middle and posterior hypospadias). Magpi, Mathieu's (flip-flap technique) and pedicled flaps tubularized or as onlay were utilized, depending upon the severity of the anomaly. RESULTS: Satisfactory functional and cosmetic results without complications were obtained in 736 cases (85.9%). We had early complications with 72 cases consisting of 64 fistulas (7. 5%) and 8 cases of breakdown (0.93%), and 48 cases of delayed complications consisting of 26 meatal retractions (3.1%) and 22 cases of meatal stenosis (2.5%).

In vitro study of drug-loaded bioresorbable films and support structures.

Bioresorbable films can serve simultaneously as anatomic support structures and as drug delivery platforms. In the present study, bioresorbable poly(L-lactic acid) (PLLA) films containing dexamethasone were prepared by solution processing methods. Their in vitro studies focused on the mechanical properties with respect to morphology and degradation and erosion processes. Novel expandable support devices (stents) developed from these films were studied. Such a stent would support conduits, such as the neonatal trachea to treat tracheal malacia, until the airway matures, and would then be totally resorbed, obviating the need for a removal operation. The PLLA films showed good initial mechanical properties. They can accommodate drug incorporation on the film surface and also in the bulk. Water incubation of the films results in a decrease in their tensile mechanical properties, due to chain scission and morphological changes. These changes can vary from degradation and small changes in morphological features to erosion, leading to a microporous structure, depending on the polymer. The cumulative release of dexamethasone from the films is linear. The rate of release is determined by the film's structure (drug location/dispersion). The stents demonstrated good mechanical properties. The initial radial compression strength of the stent is determined mainly by the polymer structure. Drug incorporation has a minor effect on the initial stent strength. Exposure to radial compression stress results in elastic reversible deformation or a sudden brittle fracture, depending on the polymer. A 20-week in vitro study of the stents showed that they are applicable for supporting body conduits, such as the trachea.