Effects of multifunctional cross-linkers on rheology and adhesion of soft nanostructured materials.

We investigate the nanostructure, the rheology and the adhesion of soft supramolecular materials elaborated by blending monofunctional and multifunctional poly(isobutene) (PIB) chains. Monofunctional PIB chains (PIBUT) are linear and unentangled polymer chains (Mn ≈ 3 kg mol-1) functionalized in the middle by a bis-urea interacting moiety, able to self-associate by four hydrogen bonds. Covalent coupling of monofunctional PIB allows us to synthesize longer chains bearing two or three interacting moieties. These chains are then added to monofunctional PIB to prepare blends containing up to 10% of multifunctional PIB (M-PIBUT). The influence of M-PIBUT on the supramolecular nanostructure, which results from the self-assembly of stickers, is studied by Atomic Force Microscopy and Small Angle X-ray Scattering at room temperature. Multifunctional and monofunctional chains are shown to interact with each other to form bundles of rod-like aggregates. The consequences of these interactions on the rheology of the blends were studied by shear tests in the linear and non linear regimes, below and above the order-disorder transition temperature. A pronounced strengthening effect of M-PIBUT is observed at room temperature: the supramolecular blends become more elastic and are more resistant to creep with increasing concentration of M-PIBUT. The effects of M-PIBUT on the nanostructure and the rheology suggest that M-PIBUT, which can link with more than one supramolecular aggregate, plays the role of a physical cross-linker. The impact of these supramolecular cross-linkers on the adhesion of the blends is studied by probe-tack tests and discussed by analyzing the in situ deformation through the debonding images.

Towards the optimization of drug delivery to the cochlear apex: Influence of polymer and drug selection in biodegradable intracochlear implants.

There is growing need for new drug delivery systems for intracochlear application of drugs to effectively treat inner ear disorders. In this study, we describe the development and characterization of biodegradable, triamcinolone-loaded implants based on poly(lactic-co-glycolic acid) (PLGA) and polyethylene glycol-poly(lactic-co-glycolic acid) (PEG-PLGA) respectively, prepared by hot-melt extrusion. PEG 1500 was used as a plasticizer to improve flexibility and accelerate drug release. The sterilization process was performed by electron beam irradiation, resulting in minimal but acceptable polymer degradation for PEG-PLGA implants. The implants have been characterized by texture analysis, differential scanning calorimetry and X-ray powder diffraction. Compared to PLGA implants, PEG-PLGA implants offer similar flexibility but with improved mechanical stability, which will ease the handling and intracochlear application. A controlled release over three months was observed for dexamethasone and triamcinolone extrudates (drug load of 10%) with similar release profiles for both drugs. PEG-PLGA implants showed an initial slow release rate over several days regardless of the amount of PEG added. Mathematical simulations of the pharmacokinetics of the inner ear based on the in vitro release kinetics indicate a complete distribution of triamcinolone in the whole human scala tympani, which underlines the high potential of the developed formulation.

'Non-criteria' aPL tests: report of a task force and preconference workshop at the 13th International Congress on Antiphospholipid Antibodies, Galveston, TX, USA, April 2010.

Abstract: Current classification criteria for definite APS recommend the use of one or more of three positive standardized laboratory assays, including anticardiolipin antibodies (aCL), lupus anticoagulant (LA), and antibodies directed to ß(2)glycoprotein I (anti-ß(2)GPI) to detect antiphospholipid antibodies (aPL) in the presence of at least one of the two major clinical manifestations (i.e., thrombosis or pregnancy morbidity) of the syndrome. Several other autoantibodies shown to be directed to phospholipids and/or their complexes with phospholipids and/or to proteins of the coagulation cascade, as well as a mechanistic test for resistance to annexin A5 anticoagulant activity, have been proposed to be relevant to APS. A task force of worldwide scientists in the field discussed and analyzed critical questions related to 'non-criteria' aPL tests in an evidence-based manner during the 13th International Congress on Antiphospholipid Antibodies (APLA 2010, 13-16 April 2010, Galveston, Texas, USA). This report summarizes the findings, conclusions, and recommendations of this task force.

[Fine specificity of anti-ß2glycoprotein I antibodies in systemic autoimmune diseases is mostly directed against domain 1]. / La fine specificità degli anticorpi anti-ß2 glicoproteina I nelle malattie autoimmune sistemiche è prevalentemente diretta verso il dominio 1.

OBJECTIVE: Anti-ß2 GPI are a formal laboratory criterion for the antiphospholipid syndrome (APS). They were demonstrated to be a risk factor for thrombosis and fetal losses but can also be detected in patients with systemic autoimmune disease (SAD), in healthy adults individuals and pre-school children. It has been suggested that different subpopulations of anti-ß2GPI may carry different pathogenetic potential: autoantibodies against Domain1 seem to be associated with thrombosis; autoantibodies against Domain4/5 have been identified in patients with non-thrombotic conditions. METHODS: We studied 48 patients with SAD (32 systemic lupus erythematosus, 16 undifferentiated connettive tissue disease), 64 patients with APS, 57 one-year-old healthy children born to mother with SAD, 33 children with atopic dermatitis. All subjects were IgG anti-ß2 GPI positive. The specificity of anti-ß2 GPI was investigated using ELISA research products containing recombinant ß2 GPI D1 and D4/5 antigens. Cut-off values are calculated as 95th percentile on 100 NHD. IgG anti-ß2 GPI were tested at a validated home-made ELISA routinely performed in our laboratory. No thrombotic events were recordered in patients with SAD and in both groups of children. RESULTS: Patients with SAD and APS showed prevalent reactivity for D1 while children in both groups preferentially recognize D4/5. CONCLUSIONS: IgG anti-ß2 GPI against D1 seem to cluster in patients with systemic autoimmune conditions. Their pathogenic potential in determine APS manifestations may be mitigated by adequate prophylaxis.

[Subpopulations of anti-ß2glycoprotein I antibodies with different pathogenic potential: fine specificity against the domains of ß2glycoprotein I]. / Sottopopolazioni di anticorpi anti-ß2glicoproteina I con diverso potenziale patogenetico: fine specificità nei confronti dei domini della ß2glicoproteina I.

OBJECTIVE: Anti-ß2glycoprotein I antibodies (a-ß2GPI) are a laboratory criterion for the antiphospholipid syndrome (APS) and were demonstrated to be involved in the pathogenesis of APS. However, they can also be detected in asymptomatic subjects. It has been suggested that a-ß2GPI against Domain1 (D1) associate with thrombosis, while those recognizing Domain4/5 (D4/5) have been identified in non-thrombotic conditions. We evaluate the specificity of a-ß2GPI in different clinical situations. METHODS: We studied 39 one-year-old healthy children born to mothers with systemic autoimmune diseases (SAD) (15 (38.4%) were born to mothers who were a-ß2GPI positive), 33 children with atopic dermatitis (AD) and 55 patients with APS (50 adults and 5 paediatrics). All subjects were IgG a-ß2GPI positive. IgG a-ß2GPI were performed by homemade ELISA, while IgG a-ß2GPI D1 and D4/5 were tested on research ELISAs containing recombinant ß2GPI domains antigens. RESULTS: One-year-old children and AD children displayed preferential reactivity for D4/5; patients with APS recognized preferentially D1. We also found a good correlation between a-ß2GPI and D4/5 in one-year-old (r=0.853) and AD children (r=0.879) and between a-ß2GPI and D1 in the APS group (r=0.575). No thrombotic events were recorded in both groups of children. CONCLUSIONS: A-ß2GPI found in non-thrombotic conditions (healthy children born to mothers with SAD and AD children) mostly recognize D4/5, in contrast to the prevalent specificity for D1 in the APS group. The different specificity could at least partially explain the "innocent" profile of a-ß2GPI in children.

Peripheral opioid analgesia.

Major recent findings in peripheral opioid analgesia include the relative lack of tolerance under inflammatory conditions, tetrapeptides as novel peripherally restricted compounds, the potent anti-inflammatory activity of mu and kappa agonists and the identification of selectins as important molecules governing the homing of opioid cells to injured tissue. Clinical studies have now moved into the field of chronic arthritic pain, a problem of major relevance and prevalence.

Effect of the peripherally selective kappa-opioid agonist, asimadoline, on adjuvant arthritis.

1. Opioids, though widely used as analgesics, have not been seriously considered as therapy for rheumatoid arthritis. The present study evaluated the dose-effect and time-dependence relationships of a new peripherally selective kappa agonist, asimadoline, in rats with adjuvant arthritis. 2. The arthritis was assessed by a pooled severity index combining the comprehensive criteria of oedema, radiography and histological changes, in the hind limbs. Asimadoline was extremely effective in attenuating joint damage (by up to 80%) when administered parenterally (0.5 to 10 mg kg(-1) day(-1), i.p.) throughout the disease or during its early phase; treatment was less successful if confined to the latter stages. Ten fold higher doses were effective orally. 3. Equimolar doses of a peripherally-selective antagonist, naloxone methiodide, and the kappa-selective antagonist, MR2266, fully reversed the peripheral anti-arthritic effects of asimadoline (5 mg kg(-1) day(-1)), indicating that asimadoline acts through peripheral kappa-opioid receptors. However, an equivalent dose of MR2266 did not fully reverse the anti-arthritic effects of the highest dose of asimadoline (40 mg kg(-1) day(-1)), suggesting a loss of kappa-selectivity at this dose. 4. Asimadoline also exhibited analgesic effects (mechanical nociceptive thresholds) in arthritic but not non-arthritic rats, indicating that inflammation is necessary for asimadoline-induced analgesia. 5. These data confirm our previous findings that kappa-opioids possess anti-arthritic properties and that these effects are mediated via peripheral kappa-receptors. The present results are new in showing that the peripherally acting kappa-opioid agonist, asimadoline, is a potent anti-arthritic agent. Such novel drugs, essentially lacking central side effects, herald new treatments for rheumatoid arthritis.

Coexistence of bullous pemphigoid and systemic lupus erythematosus.

A vesiculobullous eruption with clinical and histological features of bullous pemphigoid developed in a 28-year-old woman with proven systemic lupus erythematosus (SLE). Serum of this patient contained elevated titers of antinuclear antibodies but basement membrane antibodies could not be detected at first, though they did appear in blister fluid. Normal monkey skin explants cultured on this patient's sera gave positive direct immunofluorescence (IF) at the basement membrane zone (BMZ) for IgG deposits. The use of tissue culture methods may be helpful because of the capacity of this test system to reveal the presence of the antibodies to the BMZ despite the presence of the antinuclear antibodies that appear to interfere with their demonstration in standard indirect IF tests.

Immunopathology of psoriasis.

Immunofluorescence (IF) studies by the direct and indirect methods demonstrate immunoglobulins and complement bound in vivo in psoriatic scales. The IF pattern is comparable to that of stratum corneum antibodies (SCAb) bound in vitro on specific substrate, as visualized by the indirect IF method. Formation of immune complexes can be responsible for the "squirting papilla" phenomenon, and conversion of the stratum corneum - which is normally an inaccessible antigen - into its reactive form seems to be brought about by proteases of polymorphonuclear leukocytes. Stimulation of protease production by polymorphonuclears appears to be an important factor in the pathogenesis of psoriasis. The stratum corneum of the epidermis is probably the target, and becomes an antigen for SCAb present in the circulation.

Effect of low-dose acute X-irradiation on the frequencies of chromosomal aberrations in human peripheral lymphocytes in vitro.

In a coordinated research programme sponsored by the International Atomic Energy Agency, the frequencies of chromosomal aberrations induced in peripheral blood lymphocytes (in vitro) by 250 kV X-rays at low doses (0.4, 1, 2, 3, 5, 10 and 30 rad) were determined. Blood from 2 donors was used to conduct one master experiment at these dose levels. The culture time used was 48 h and all samples including the controls were processed according to a standard protocol. The coded slides were scored by investigators from 10 participating laboratories. The main results are the following: (1) the frequencies of all types of chromosome aberrations at 0.4 rad are significantly lower than the control values; (2) there is no increase in the frequencies of dicentrics up to 2 rad and in those of terminal deletions up to 5 rad; (3) the mean frequencies of all aberrations considered together are not significantly different from one another at 1, 2 and 3 rad (P = 0.05); and (4) over the entire dose range the dose-effect relationship is clearly non-linear. A fit of these data to a linear quadratic model (E(D) = c + alpha D + beta D2) showed that the observed total aberration frequencies at doses 1, 2, 3 and 5 rad are below the curve defined by the model. The deviations can be explained by an altered kinetics of aberration production at very low doses probably due to DNA repair mechanisms operating these cells.

Mentoplasty--a clinical analysis of alloplastic implants.

Different types of alloplastic implants are currently being utilized in performing mentoplasty. A review of the literature points out the number of prostheses that have been used. Each type of material has inherit physical properties which determine its characteristics for use as a chin implant. The type of implant and method selected in chin augmentation depends upon accurate preoperative evaluation and full understanding of the properties of alloplastic substances. Five hundred and thirty-nine cases of chin augmentation utilizing different materials and methods were reviewed over a nine year period. The limitations of mentoplasty as well as the advantages, disadvantages, and in selected cases, the indications for the use of a particular implant are discussed.

Submalar augmentation. An alternative to face-lift surgery.

Submalar augmentation is a new approach that effectively deals with many of the problems encountered in midfacial rejuvenation. This study reports the results of 78 patients who were successfully treated over 6 years by submalar augmentation. This procedure consists of inserting newly designed Silastic (silicone rubber) implants over the midface to create the appearance of restoring the vibrant and youthful fullness of the middle third of the face while avoiding distortion of normal facial anatomy. When used alone, it provides an alternative to rhytidectomy in the 38- to 50-year age group. The benefits of submalar augmentation are such that it should be considered a standard part of the surgical approach to facial rejuvenation.

The management of hyperfunctional facial lines with botulinum toxin. A collaborative study of 210 injection sites in 162 patients.

OBJECTIVE: To determine the optimum dose and efficacy of botulinum toxin injections in the management of hyperfunctional facial lines. DESIGN: This study included 210 hyperfunctional facial sites in 162 different patients. The patients had preinjection and postinjection photographic documentation and ratings on a 4-point qualitative evaluation scale of lines at rest and with action. The patients then had botulinum toxin type A injections via a monopolar hollow bore, Teflon-coated electromyographic needle into the facial muscles associated with the hyperfunctional lines. The total dose for each region of 1.25 to 25 U was divided into 1.25- to 5-U aliquots representing 0.1 to 0.2 mL per injection site, depending on the site and the prior experience with that patient on using toxin. The patients had their reevaluation at 2 to 3 weeks after injection. Patients returned for further follow-up when the therapeutic effect diminished. PATIENTS: One hundred sixty-two patients had 210 hyperfunctional sites evaluated and injected. The group consisted of 25 male patients and 137 female patients ranging in age from 21 to 78 years with a mean (+/-SD) of 46.1 (+/-1.98) years. All patients had cosmetically troubling hyperfunctional lines involving the forehead, glabella, crow's feet (lateral canthal lines), nasolabial area, platysma, and mentalis region. RESULTS: All patients had an effect of toxin within the first 24 to 72 hours. Ninety-five percent of the patients treated had cosmetic improvement of unsightly facial lines or contractions. The best results were achieved in management of the forehead lines, followed by glabella, crow's feet, and nasolabial. The dose for forehead lines was 5 to 25 U (mean +/- SD, 17.3 +/- 6.2 U); glabellar lines, 5 to 20 U (mean +/- SD, 11.1 +/- 3.1 U); crow's feet, 5 to 15 U (mean +/- SD, 6.2 +/- 1.6 U); nasolabial, 2.5 to 5 U (mean +/- SD, 3.12 +/- 1.2 U); and platysma, 10 to 20 (mean +/- SD, 15 +/- 4.0 U). Evaluation by age and site suggested a trend of increased toxin dose with increased age. Effects of the toxin are usually seen 24 to 72 hours after injection, and last from 3 to 6 months, whereon the increased muscular activity returns, as do the hyperfunctional lines. The only morbidity was related to temporary mild weakness of other adjacent facial muscles. There were no systemic side effects noted. CONCLUSION: Botulinum toxin is a safe and important adjunctive technique for the management of patients with symptomatic hyperfunctional facial lines.

Lumbar discography. Its value in diagnosis and treatment of lumbar disc lesions.

Lumbar discography has been performed in over 1500 patients at St. Luke's Episcopal Hospital, and a report concerning 683 cases has been previously published. The authors review an additional 199 cases, finding that decision making was influenced by discography in 155 cases (78%). A positive discogram was surgically confirmed in 111 patients (56%). In 14(7%) the disc was found to be normal at surgery. One hundred six patients (53%) had positive discograms with negative or equivocal myelogram. In 36 patients with a positive myelogram, the discogram was corroborative, although most patients with positive myelograms did not have discography. Sixty-nine patients (35%) did not have surgery.

Autoamputation of the first sacral nerve roots in spondyloptosis.

To our knowledge, this is the first reported case of bilateral autoamputation of the first sacral nerve roots in a patient who has spondyloptosis. The authors think that autoamputation occurred in adolescence during a period of rapid forward displacement of the fifth lumbar vertebra on the sacrum. It is postulated that the lack of motor weakness is due to the long-standing nature of the denervation and that other adjacent nerve roots supplying the triceps surae have, over time, increased the power of those muscle fibers not supplied by the first sacral roots. This finding would encourage development of methods for early reduction and fusion in children showing marked restriction of straight leg raising (ie, tight hamstrings) to prevent rapid listhesis and fixation of the fifth lumbar vertebra to the sacrum.

Current concepts and diagnostic evaluation of autoimmune disease.

This article discusses autoimmune reactions and the numerous mechanisms by which an autoimmune response may be initiated, including genetic factors, T-cell bypass mechanisms, and idiotypes. Human autoimmune diseases are classified into three main groups, ie, organ-specific, non-organ specific, and disorders with non-organ-specific autoantibodies with lesions restricted to one or a few organs, that are examined in detail. General laboratory tests and interpretation of results in relation to state or treatment of the particular disease, age and sex of the patient, and the sensitivity of the test system used are reviewed.

Botulinum toxin type A (BOTOX) for treatment of migraine headaches: an open-label study.

OBJECTIVE: The object of this clinical experience was to evaluate the correlation between pericranial botulinum toxin type A (BOTOX, Allergan Corp, Irvine, CA) administration and alleviation of migraine headache symptoms. STUDY DESIGN AND SETTING: A nonrandomized, open-label study was performed at 4 different test sites. The subjects consisted of 106 patients, predominantly female, who either (1) initially sought BOTOX treatment for hyperfunctional facial lines or other dystonias with concomitant headache disorders, or (2) were candidates for BOTOX treatment specifically for headaches. Headaches were classified as true migraine, possible migraine, or nonmigraine, based on baseline headache characteristics and International Headache Society criteria. BOTOX was injected into the glabellar, temporal, frontal, and/or suboccipital regions of the head and neck. Main outcome measures were determined by severity and duration of response. The degrees of response were classified as: (1) complete (symptom elimination), (2) partial > or =50% reduction in headache frequency or severity), and (3) no response [neither (1) nor (2)]. Duration of response was measured in months for the prophylactic group. RESULTS: Among 77 true migraine subjects treated prophylactically, 51% (95% confidence interval, 39% to 62%) reported complete response with a mean (SD) response duration of 4.1 (2.6) months; 38% reported partial response with a mean (SD) response duration of 2.7 (1.2) months. Overall improvement was independent of baseline headache characteristics. Seventy percent (95% confidence interval, 35% to 93%) of 10 true migraine patients treated acutely reported complete response with improvement 1 to 2 hours after treatment. No adverse effects were reported. CONCLUSIONS: BOTOX was found to be a safe and effective therapy for both acute and prophylactic treatment of migraine headaches. Further research is needed to explore and develop the complete potential for the neuroinhibitory effects of botulinum toxin.

Reconstruction of posttraumatic and congenital facial deformities with three-dimensional computer-assisted custom-designed implants.

The principles, method, and benefits of combining three-dimensional computed tomography (CT) and computer-aided design/computer-aided manufacture (CAD/CAM) technology for development of custom-designed prostheses are applied in the repair of posttraumatic and congenital facial contour deficiencies. Each prosthesis is generated to fit the bone defect exactly, with external contours adjusted to compensate for overlying soft-tissue disparities. Three representative case reports from a series of 17 demonstrate the applications and advantages of using this technique. Some patients had residual defects after primary repair of posttraumatic deformities. Others had defects after orthognathic relapses for congenital deformities. Without a relatively minor surgery and a high degree of predictability, many of these patients would not have pursued further treatment. All but one of the surgeries were performed on an outpatient basis, providing an accurate, simple, and cost-effective method of contour restoration with limited morbidity and reduced operative time.

Botulinum toxin A for hyperkinetic facial lines: results of a double-blind, placebo-controlled study.

Previous work on patients with muscular dystonia has shown that small intramuscular doses of botulinum toxin A eliminated hyperkinetic facial lines for approximately 6 months. The purpose of this study was to determine the efficacy of botulinum toxin A injections in eliminating facial wrinkles in aesthetic surgery patients who do not have muscular dystonia. Eleven healthy subjects were studied in a double-blind fashion. On both sides of the face, 0.2 cc of either normal saline or botulinum toxin A was injected into the forehead or into the periorbital wrinkles (crow's feet). Documentation of results was made by photographs taken of the patients during repose and during facial animation before and after injection. Assessment of facial wrinkles was done from a grading system in which the patient and the facial plastic surgeon were asked to judge the severity of the wrinkles on a scale from 0 to 3, with 0 reflecting no facial wrinkles and 3 reflecting severe facial wrinkling. Nine of 11 subjects injected with botulinum toxin A noted a significant improvement in the severity of their facial wrinkles in comparison with the side of the face injected with saline, with a rating improvement of 2 points. Two of 11 subjects noted a moderate improvement, with a rating improvement of 1 point. No patient injected with saline reported an improvement in the severity of the facial wrinkles on the control side. There were no serious complications. Botulinum toxin A is an efficacious method of nonsurgically eliminating facial wrinkles and may play a role in the cosmetic enhancement of the aging face.

Mucoepidermoid carcinoma of the larynx. A case report and review of the literature.

A case report of mucoepidermoid carcinoma of the larynx is presented and the literature reviewed. The inherent difficulties in histologic diagnosis are noted and the clinical behavior and treatment of mucoepidermoid carcinoma are discussed. At the present time, mucoepidermoid carcinoma of the larynx should be regarded as a separate entity, its treatment based on histological grade as well as clinical behavior.