Double-handed endoscopic myringoplasty with a holding system in children: Preliminary observations.

OBJECTIVES: Endoscopic transcanal myringoplasty is a newly-introduced technique for reconstruction of tympanic membrane perforation that offers the advantage to obviate postauricular incision. The objective of this study was to evaluate the feasibility of a double-handed endoscope holder transcanal myringoplasty in children. This technique permits bimanual execution of the procedure and allows the surgeon to overcome the two significant issues of single-handed endoscope surgery, i.e. easy domination of a bloody field and smooth introduction of the graft. METHODS: A prospective non-randomized study of 10 consecutive primary endoscope holder-aided myringoplasties was performed; 3 mm or 4 mm 0° rigid endoscopes were used. A xenograft, biologic soft tissue, was applied in all cases. RESULTS: All procedures were performed successfully. Duration of surgery was faster than with a single-handed procedure and varied between 20 and 60 min. The tympanic membrane healed successfully in all patients. CONCLUSIONS: In this preliminary experience in children, a bimanual endoscopic holder-aided myringoplasty technique offers the possibility to overcome the obstacles encountered in a single-handed technique, since it can replicate the same concept of a bimanual microscopic approach and allow for easy management of a bloody field and introduction of the graft in the middle ear.

Multiple myeloma causes clonal T-cell immunosenescence: identification of potential novel targets for promoting tumour immunity and implications for checkpoint blockade.

Tumour-induced dysfunction of cytotoxic T cells in patients with multiple myeloma (MM) may contribute to immune escape and be responsible for the lack of therapeutic efficacy of immune checkpoint blockade. We therefore investigated dysfunctional clonal T cells in MM and demonstrated immunosenescence but not exhaustion as a predominant feature. T-cell clones were detected in 75% of MM patients and their prognostic significance was revalidated in a new post-immunomodulatory drug cohort. The cells exhibited a senescent secretory effector phenotype: KLRG-1+/CD57+/CD160+/CD28-. Normal-for-age telomere lengths indicate that senescence is telomere independent and potentially reversible. p38-mitogen-activated protein kinase, p16 and p21 signalling pathways known to induce senescence were not elevated. Telomerase activity was found to be elevated and this may explain how normal telomere lengths are maintained in senescent cells. T-cell receptor signalling checkpoints were normal but elevated SMAD levels associated with T-cell inactivation were detected and may provide a potential target for the reversal of clonal T-cell dysfunction in MM. Low programmed death 1 and cytotoxic T-lymphocyte-associated antigen 4 expression detected on T-cell clones infers that these cells are not exhausted but suggests that there would be a suboptimal response to immune checkpoint blockade in MM. Our data suggest that other immunostimulatory strategies are required in MM.

Genetic variants of SLC11A1 are associated with both autoimmune and infectious diseases: systematic review and meta-analysis.

A systematic review and meta-analyses were undertaken to investigate the association of SLC11A1 genetic variants with disease occurrence. Literature searching indentified 109 publications to include in the meta-analyses assessing the association of 11 SLC11A1 variants with autoimmune and infectious disease. The (GT)n promoter alleles 2 and 3 (rs534448891), which alter SLC11A1 expression, were significantly associated with tuberculosis (OR=1.47 (1.30-1.66), OR=0.76 (0.65-0.89), respectively) and infectious disease (OR=1.25 (1.10-1.42), OR=0.83 (0.74-0.93), respectively). However, although no association was observed with autoimmune disease, a modest significant association was observed with type 1 diabetes (allele 2 OR=0.94 (0.89-0.98)). On the basis of a stronger association of (GT)n allele 2 with tuberculosis, compared with the protective effect of allele 3, we hypothesise that allele 2 is likely the disease-causing variant influencing disease susceptibility. Significant associations were observed between the 469+14G/C polymorphism (rs3731865) and autoimmune disease (OR=1.30 (1.04-1.64)) and rheumatoid arthritis (OR=1.60 (1.20-2.13)) and between the -237C/T polymorphism (rs7573065) and inflammatory bowel disease (OR=0.60 (0.43-0.84)). Further, significant associations were identified between the 469+14G/C, 1730G/A and 1729+55del4 polymorphisms (rs3731865, rs17235409 and rs17235416, respectively) and both infectious disease per se and tuberculosis. These findings show a clear association between variants in the SLC11A1 locus and autoimmune and infectious disease susceptibility.

Factors affecting residual hearing preservation in cochlear implantation.

The likelihood of residual hearing preservation in cochlear implantation (CI) is related to surgical factors such as type of cochleostomy (trans-fenestral vs. promontorial), use of lubricants and protective drugs, and device-related factors such as shape, length and flexibility of the array. We investigated the impact of these factors on the hearing preservation rate in adults and children with conventional audiological indications to CI. Eighty-two children aged 1-9 years and 73 adults (16-79 years) received a CI in the right (59%) or left ear (41%). An anterior-inferior promontorial cochleostomy was performed in 143 ears (92%); a trans-fenestral approach was used in 12 (8%). A perimodiolar electrode was implanted in 144 ears (93%), and a straight electrode in the remaining 11 (7%). Overall, some post-operative hearing was retained in 39% of ears. The rate of preservation was higher at the low than at the high frequencies. When correlated with age, side of implant, implant model and type of cochleostomy, the mean threshold variations did not reach statistical significance for any of these variables. A slight trend in favour of better residual hearing preservation in children vs. adults was seen, especially at lower frequencies.

Use of mini dental implants in ectodermal dysplasia children: follow-up of three cases.

BACKGROUND: Ectodermal dysplasia is a hereditary genodermatosis characterised by a congenital defect of ectodermal structures, causing tooth malformations and anomalies. Implantology has become accepted in these subjects. However cases are often complicated by a reduction in the size of the alveolar process, making the insertion of conventional implants difficult without bone grafting. The reduced diameter of mini-implants and their ease of insertion provide an interesting solution in supporting removable or fixed prosthesis. The purpose of this paper is to report the follow-up of three cases of children (11-12 year- old) with ectodermal dysplasia in which mini-implants were used to support the prostheses. CASE REPORTS: In the first case, two mini-implants were inserted into the anterior part of the mandible for stabilising a removable denture (2 years follow-up). In the other two cases, mini- implants were inserted in the maxilla and mandible to replace missing front teeth with fixed prostheses. Patients were called for follow- up every 6 months: in the sencod case follow-up lasted 4 years in the mandible and 2 years in the maxilla; in the third case, 2 years in the maxilla and 1 year in the mandible. CONCLUSION: The use of mini-implants in children with ectodermal dysplasia can enhance aesthetics, and functional and psychosocial development.

Long-term survival in multiple myeloma is associated with a distinct immunological profile, which includes proliferative cytotoxic T-cell clones and a favourable Treg/Th17 balance.

Despite improved outcomes in multiple myeloma (MM), a cure remains elusive. However, even before the current therapeutic era, 5% of patients survived >10 years and we propose that immune factors contribute to this longer survival. We identified patients attending our clinic, who had survived >10 years (n=20) and analysed their blood for the presence of T-cell clones, T-regulatory cells (Tregs) and T helper 17 (Th17) cells. These results were compared with MM patients with shorter follow-up and age-matched healthy control donors. The frequency of cytotoxic T-cell clonal expansions in patients with <10 years follow-up (MM patients) was 54% (n=144), whereas it was 100% (n=19/19) in the long-survivors (LTS-MM). T-cell clones from MM patients proliferated poorly in vitro, whereas those from LTS-MM patients proliferated readily (median proliferations 6.1% and 61.5%, respectively (P<0.0001)). In addition, we found significantly higher Th17 cells and lower Tregs in the LTS-MM group when compared with the MM group. These results indicate that long-term survival in MM is associated with a distinct immunological profile, which is consistent with decreased immune suppression.

Pancreatic transdifferentiation in porcine liver following lentiviral delivery of human furin-cleavable insulin.

Type I diabetes mellitus (TID) results from the autoimmune destruction of the insulin-producing pancreatic ß-cells. Gene therapy is one strategy being actively explored to cure TID by affording non-ß-cells the ability to secrete insulin in response to physiologic stimuli. In previous studies, we used a novel surgical technique to express furin-cleavable human insulin (INS-FUR) in the livers of streptozotocin (STZ)-diabetic Wistar rats and nonobese diabetic (NOD) mice with the use of the HMD lentiviral vector. Normoglycemia was observed for 500 and 150 days, respectively (experimental end points). Additionally, some endocrine transdifferentiation of the liver, with storage of insulin in granules, and expression of some ß-cell transcription factors (eg, Pdx1, Neurod1, Neurog3, Nkx2-2, Pax4) and pancreatic hormones in both studies. The aim of this study was to determine if this novel approach could induce liver to pancreatic transdifferentiation to reverse diabetes in pancreatectomized Westran pigs. Nine pigs were used in the study, however only one pig maintained normal fasting blood glucose levels for the period from 10 to 44 days (experimental end point). This animal was given 2.8 × 10(9) transducing units/kg of the lentiviral vector expressing INS-FUR. A normal intravenous glucose tolerance test was achieved at 30 days. Reverse-transcription polymerase chain reaction analysis of the liver tissue revealed expression of several ß-cell transcription factors, including the key factors, Pdx-1 and Neurod1, pancreatic hormones, glucagon, and somatostatin; however, endogenous pig insulin was not expressed. Triple immunofluorescence showed extensive insulin expression, as was previously observed in our studies with rodents. Additionally, a small amount of glucagon and somatostatin protein expression was seen. Collectively, these data indicate that pancreatic transdifferentiation of the liver tissue had occurred. Our data suggest that this regimen may ultimately be used clinically to cure TID, however more work is required to replicate the successful reversal of diabetes in increased numbers of pigs.

Prenatal depression leading to postpartum psychosis.

Postpartum psychosis is a mood disorder occurring up to 3 months after delivery. Incidence is one to two women every 1,000 live births. If not detected and appropriately treated in time, it may have detrimental effects on both the mother and her baby. We report a case of puerperal psychosis in a patient with a history of depression. We have also reviewed the relevant literature discussing prediction, management and differential diagnosis of postpartum psychosis. We emphasise the importance of early detection and provision of care to all women at risk of mental illness by multidisciplinary team, including GPs, obstetricians, midwives and perinatal mental health professionals.

Long-term correction of diabetes in rats after lentiviral hepatic insulin gene therapy.

AIMS/HYPOTHESIS: Type 1 diabetes results from the autoimmune destruction of pancreatic beta cells. Exogenous insulin therapy cannot achieve precise physiological control of blood glucose concentrations, and debilitating complications develop. Lentiviral vectors are promising tools for liver-directed gene therapy. However, to date, transduction rates in vivo remain low in hepatocytes, without the induction of cell cycling. We investigated long-term transgene expression in quiescent hepatocytes in vitro and determined whether the lentiviral delivery of furin-cleavable insulin to the liver could reverse diabetes in rats. MATERIALS AND METHODS: To improve transduction efficiency in vitro, we optimised hepatocyte isolation and maintenance protocols and, using an improved surgical delivery method, delivered furin-cleavable insulin alone or empty vector to the livers of streptozotocin-induced diabetic rats by means of a lentiviral vector. Rats were monitored for changes in body weight and blood glucose, and intravenous glucose tolerance tests were performed. Expression of insulin was determined by RT-PCR, immunohistochemistry and electron microscopy. RESULTS: We achieved long-term transgene expression in quiescent hepatocytes in vitro (87 +/- 1.2% transduction efficiency), with up to 60 +/- 3.2% transduction in vivo. We normalised blood glucose for 500 days-a significantly longer period than previously reported-making this the first successful study using a lentiviral vector. This procedure resulted in the expression of genes encoding several beta cell transcription factors, some pancreatic endocrine transdifferentiation, hepatic insulin storage in granules, and restoration of glucose tolerance. Liver function tests remained normal. Importantly, pancreatic exocrine transdifferentiation did not occur. CONCLUSIONS/INTERPRETATION: Our data suggest that this regimen may ultimately be employed for the treatment of type 1 diabetes.

[Interceptive treatments for deformities in the vertical dimension]. / Traitements interceptifs des dysmorphies dans la dimension verticale.

Vertical dimension deformities result from an interference of multiple etiological factors acting during the growth period. They include maxillary and mandibular growth, dento-alveolar compensations as well as the functional environment. These deformities do not work in total isolation, but usually combine with others present in sagittal and transverse dimensions. Our intervention has to be three-dimensional and take into consideration the interaction of the three dimensions of space. It must address soft tissue components as well as the dento-alveolar and the skeletal ones of the maxilla and the mandible. Interceptive treatment of vertical dimension deformities rests on two pillars: the diagnosis and therapeutics. The diagnostic pillar aims to show how different structures relate to each other as well as with neighboring structures. These structures consist of the soft tissue components that will eventually control the smile, the dento-alveolar component that influences occlusal plane inclination and the skeletal component that determines the vertical facial type. Using this analysis, we classify our patients in categories that facilitate our later therapeutic intervention. The therapeutic pillar is constructed in an attempt to find solutions for the list of problems established during diagnosis and to encourage development of logical individualized thinking, independently of the orthodontic technique used. All of this underlines the importance of choosing an Individualized Orthodontic Therapy based upon concepts that respond to different individual clinical situations and work most effectively to achieve treatment objectives.

Ultra-high speed and ultra-high resolution spectral-domain optical coherence tomography and optical Doppler tomography in ophthalmology.

We present ultra-high resolution optical coherence tomography (OCT) structural intensity and optical Doppler tomography (ODT) flow velocity images of the human retina in vivo. The ultra-high speed OCT system is based on Spectral Domain or Fourier Domain technology, which provides a sensitivity advantage over conventional OCT of more than 2 orders of magnitude. This sensitivity improvement allows video rate OCT and ODT cross sectional imaging of retinal structures. Images will be presented with axial resolutions of 6 and 3.5 microns. We observed small features in the inner and outer plexiform layers, which are believed to be small blood vessels. Flow velocity images will be presented showing pulsatile flow in retinal arteries and veins.

Full-mouth rehabilitation following treatment of temporomandibular disorders and teeth-related signs and symptoms.

The literature is replete with theories regarding temporomandibular disorders (TMD). However, there is a paucity of information concerning perceived malocclusion and other teeth-related signs and symptoms after full-mouth rehabilitation. This clinical study was designed to evaluate the perception of TMD patients concerning perceived malocclusion and other teeth-related signs and symptoms after full-mouth rehabilitation guided by the Mental Analog Scale (MAS). Among 38 patients referred for full-mouth rehabilitation, 20 were diagnosed as having TMD after reviewing a questionnaire, recording the major complaints and symptoms, in addition to performing comprehensive clinical examination. Nonsurgical therapy was performed, including fabricating an anterior programming device, a centric relation occlusal device and finally full-mouth rehabilitation by means of placing crowns on all upper and/or lower teeth. All full-mouth rehabilitation procedures were performed using a fully adjustable articulator and mandibular movements were recorded following pantographic tracings. After full-mouth rehabilitation, the patients were followed up at 1, 2, 4, 6, 9, and 12-month intervals, and the major signs and symptoms were recorded along with adjunctive teeth-related signs and symptoms. Fisher exact probability tests were applied to analyze the results (P<.05). Statistical comparisons of the MAS responses before and after treatment (at 1-month recall) showed significant improvement (P<.05) for all teeth-related signs and symptoms except for bruxism (P=.0699). Further improvement was noted at the 4-month recall period. However, these improvements were not statistically significant for all teeth-related signs and symptoms. No further change was noted after the 4-month recall period. There was a marked reduction in perceived malocclusion and adjunctive teeth-related signs and symptoms during function, only after performing occlusal equilibration of the final restorations.

In vivo high-resolution video-rate spectral-domain optical coherence tomography of the human retina and optic nerve.

An ultra-high-speed spectral-domain optical coherence tomography system (SD-OCT) was developed for imaging the human retina and optic nerve in vivo at a sustained depth profile (A-line) acquisition speed of 29 kHz. The axial resolution was 6 microm in tissue and the system had shot-noise-limited performance with a maximum sensitivity of 98.4 dB. 3-dimensional data sets were collected in 11 and 13 seconds for the macula and optic nerve head respectively and are presented to demonstrate the potential clinical applications of SD-OCT in ophthalmology. Additionally, a 3-D volume of the optic nerve head was constructed from the acquired data and the retinal vascular network was visualized.

The prevalence and treatment needs of symptoms and signs of temporomandibular disorders among young adult males.

A temporomandibular disorder (TMD) screening history and screening examination was performed on 523 young adult males. The screening forms were similar to those TMD forms developed and formulated under the auspices of the American College of Prosthodontists. In turn, the substance of the latter forms was initially derived from the recommendations of the President's TMD Conference of the American Dental Association, with 62 eminent researchers, educators and clinicians as participants. Each subject was given a TMD self-administered screening history form to complete, formatted in a check - the block format. It included all items considered to be classic TMD symptoms. The screening examination was performed extraorally and included (i) range of jaw movement, (ii) digital palpation of selected masticatory muscles and palpation over the pre-auricular temporomandibula joint (TMJ) area and (iii) digital palpation for TMJ sounds during jaw movement. The subjects were categorized into the following four categories: 0 = no symptoms/signs, 1 = insignificant moderate symptoms and/or signs, 2 = significant moderate symptoms and/or signs, and 3 = severe symptoms and/or signs. The overall results showed that 75% of the subjects had TMD symptoms and/or signs. There were 6.9% in category 1, 51.4% in category 2, and 16.7% in category 3. It was recommended that subjects in category 2 and 3 should have a comprehensive TMD evaluation, in order to further identify the recommended need for TMD Therapy.

Silica-alginate composites for microencapsulation.

Optimisation of membrane properties of alginate microcapsules is a key factor for the application of microencapsulation techniques to bioartificial organ elaboration. Coacervation and layer-by-layer processes involving additional biopolymers have been extensively studied. Recently, the use of silica as a membrane-forming agent was investigated. This approach was rendered possible by the development of biocompatible routes to silica formation. The composites exhibit enhanced mechanical and thermal stability as well as suitable diffusion properties. Moreover, encapsulated enzymes and cells retain their biological activities. Similarly, silica can be associated to many other biopolymers, opening a promising route for new biocomposites design and biotechnology applications.

Surgical repair of bone defects of the ear canal wall with flexible hydroxylapatite sheets: a pilot study.

OBJECTIVE: Evaluation of suitability of flexible composite sheets (hydroxylapatite and polymer) for outer ear canal (OEC) wall reconstruction in tympanoplasty. STUDY DESIGN: Prospective, open label pilot study. SETTING: University and regional hospital. PATIENTS: Forty-two randomly selected patients with chronic otitis media (n = 20) and cholesteatoma (n = 22) among 356 patients admitted between 1996 and 1997. INTERVENTIONS: Eradication of disease through a partial or total canal wall down mastoidectomy; immediate reconstruction of canal wall with flexible composite sheet (hydroxylapatite and polymer) and connective tissue graft. OUTCOME MEASURES: Anatomic integrity of the OEC and neotympanum, extrusion rate, complications. RESULTS: At minimum follow-up of 24 months: recurrent cholesteatoma (n = 0), residual cholesteatoma (n = 3/22) (13.6%) in the mesotympanum (none behind the hydroxylapatite sheet or in the attic or antrum). The neotympanum was intact in 38 ears (90.4%), reperforated in 2, and severely retracted and lateralized in 1, respectively. Anatomic integrity of the OEC was obtained in 37 (88%) of 42 patients; stenosis or membranous synechiae were observed in 5 ears and treated in the office. Extrusion of the hydroxylapatite sheet occurred in 7 patients (16.6%) because of purulent otorrhea and granulation tissue formation. Surgical revision achieved complete epithelialization of the rebuilt canal wall in 33 ears (78.6%). CONCLUSIONS: A dry, disease-free ear and normal anatomy may be expected 2 years postoperatively in more than three-fourths of the patients treated using the described surgical technique. Complete protection with a connective tissue graft is essential to avoid extrusion of the implant. The failure rate is significantly higher if otorrhea is present at the time of the operation.