Sound therapy for cochlear implant users with tinnitus.

OBJECTIVE: Despite the positive effect of a cochlear implant (CI) on tinnitus in many patients, tinnitus remains a problem for a significant proportion of CI users. We investigated the acceptability and effect of sound therapy (a combination of natural background sounds and one concise tinnitus counselling session) on tinnitus and speech perception in CI users who still experienced tinnitus during CI use. DESIGN AND STUDY SAMPLE: Thirty-two CI users (32-78 years) participated in phase 1: a test at the clinic to evaluate six background sounds provided by the sound processor. Eighteen out of the 32 CI users participated in phase 2: an optional take-home evaluation of 2 weeks without sound therapy, followed by 5 weeks with sound therapy, ending with an evaluation visit. RESULTS: Thirty subjects (93.8%) found at least one background sound acceptable. In phase 2, a small improvement with sound therapy was found for tinnitus loudness, annoyance, and intrusiveness. 50% of the subjects subjectively reported benefit of sound therapy. Especially the sense of control on their tinnitus was highly appreciated. No detrimental effect on speech perception was observed. CONCLUSION: The background sounds were acceptable and provided tinnitus relief in some CI users with tinnitus during CI use.

The effect of tinnitus specific intracochlear stimulation on speech perception in patients with unilateral or asymmetric hearing loss accompanied with tinnitus and the effect of formal auditory training.

OBJECTIVES: Previous studies show that intracochlear electrical stimulation independent of environmental sounds appears to suppress tinnitus, even long-term. In order to assess the viability of this potential treatment option it is essential to study the effects of this tinnitus specific electrical stimulation on speech perception. DESIGN: A randomised, prospective crossover design. STUDY SAMPLE: Ten patients with unilateral or asymmetric hearing loss and severe tinnitus complaints. RESULTS: The audiological effects of standard clinical CI, formal auditory training and tinnitus specific electrical stimulation were investigated. Results show that standard clinical CI in unilateral or asymmetric hearing loss is shown to be beneficial for speech perception in quiet, speech perception in noise and subjective hearing ability. Formal auditory training does not appear to improve speech perception performance. However, CI-related discomfort reduces significantly more rapidly during CI rehabilitation in subjects receiving formal auditory training. Furthermore, tinnitus specific electrical stimulation has neither positive nor negative effects on speech perception. CONCLUSIONS: In combination with the findings from previous studies on tinnitus suppression using intracochlear electrical stimulation independent of environmental sounds, the results of this study contribute to the viability of cochlear implantation based on tinnitus complaints.

Long-lasting fibrin matrices ensure stable and functional angiogenesis by highly tunable, sustained delivery of recombinant VEGF164.

Clinical trials of therapeutic angiogenesis by vascular endothelial growth factor (VEGF) gene delivery failed to show efficacy. Major challenges include the need to precisely control in vivo distribution of growth factor dose and duration of expression. Recombinant VEGF protein delivery could overcome these issues, but rapid in vivo clearance prevents the stabilization of induced angiogenesis. Here, we developed an optimized fibrin platform for controlled delivery of recombinant VEGF, to robustly induce normal, stable, and functional angiogenesis. Murine VEGF164 was fused to a sequence derived from α2-plasmin inhibitor (α2-PI1-8) that is a substrate for the coagulation factor fXIIIa, to allow its covalent cross-linking into fibrin hydrogels and release only by enzymatic cleavage. An α2-PI1-8-fused variant of the fibrinolysis inhibitor aprotinin was used to control the hydrogel degradation rate, which determines both the duration and effective dose of factor release. An optimized aprotinin-α2-PI1-8 concentration ensured ideal degradation over 4 wk. Under these conditions, fibrin-α2-PI1-8-VEGF164 allowed exquisitely dose-dependent angiogenesis: concentrations ≥25 µg/mL caused widespread aberrant vascular structures, but a 500-fold concentration range (0.01-5.0 µg/mL) induced exclusively normal, mature, nonleaky, and perfused capillaries, which were stable after 3 mo. Optimized delivery of fibrin-α2-PI1-8-VEGF164 was therapeutically effective both in ischemic hind limb and wound-healing models, significantly improving angiogenesis, tissue perfusion, and healing rate. In conclusion, this optimized platform ensured (i) controlled and highly tunable delivery of VEGF protein in ischemic tissue and (ii) stable and functional angiogenesis without introducing genetic material and with a limited and controllable duration of treatment. These findings suggest a strategy to improve safety and efficacy of therapeutic angiogenesis.

Tinnitus Suppression by Intracochlear Electrical Stimulation in Single-Sided Deafness: A Prospective Clinical Trial - Part I.

Cochlear implantation is a viable treatment option for tinnitus, but the underlying mechanism is yet unclear. Is the tinnitus suppression due to the reversal of the assumed maladaptive neuroplasticity or is it the shift in attention from the tinnitus to environmental sounds and therefore a reduced awareness that reduces tinnitus perception? In this prospective trial, 10 patients with single-sided deafness were fitted with a cochlear implant to investigate the effect of looped intracochlear electrical stimulation (i.e. stimulation that does not encode environmental sounds) on tinnitus, in an effort to find optimal stimulation parameters. Variables under investigation were: amplitude (perceived stimulus loudness), anatomical location inside the cochlea (electrode/electrodes), amplitude modulation, polarity (cathodic/anodic first biphasic stimulation) and stimulation rate. The results suggest that tinnitus can be reduced with looped electrical stimulation, in some cases even with inaudible stimuli. The optimal stimuli for tinnitus suppression appear to be subject specific. However, medium-to-loud stimuli suppress tinnitus significantly better than soft stimuli, which partly can be explained by the masking effect. Although the long-term effects on tinnitus would still have to be investigated and will be described in part II, intracochlear electrical stimulation seems a potential treatment option for tinnitus in this population.

Optimizing intracochlear electrical stimulation to suppress tinnitus.

OBJECTIVES: Research on tinnitus suppression by intracochlear electrical stimulation has gained interest over the past few decades and it has become easier to apply since the introduction of cochlear implants (CI). This study attempted to gain more insight into optimal stimulation characteristics for tinnitus suppression. DESIGN: Eleven subjects with unilateral CI and tinnitus were recruited from our CI clinic. Electrical stimulation, independent of acoustic sounds, was generated using their CI. The current prospective (single blinded) experimental study systematically assessed two stimulation parameters, namely current level and the anatomical stimulation site inside the cochlea and their short-term effect on tinnitus. RESULTS: Approximately one-third of the tested conditions were successful in which case tinnitus loudness was reduced by at least 30%. At least one successful condition was achieved for nine subjects (82%). Complete suppression was achieved in 6 out of 107 tested conditions (6%). The effect of subthreshold electrical stimulation on tinnitus suppression did not differ significantly from above threshold electrical stimulation. However, a positive relation between mean percentage tinnitus suppression and current level was observed. Pitch-matched electrical stimulation did not appear to suppress tinnitus better than other tested conditions. CONCLUSIONS: The majority of the subjects were able to experience tinnitus reduction through intracochlear electrical stimulation independent of acoustic sounds. Tinnitus can be reduced with audible or even inaudible, subthreshold stimuli. Clear trends in optimal stimulation characteristics were not found. Optimal stimulus characteristics for tinnitus reduction therefore appear to be highly subject-specific.

Lateral temperature spread of monopolar, bipolar and ultrasonic instruments for robot-assisted laparoscopic surgery.

OBJECTIVE: To assess critical heat spread of cautery instruments used in robot-assisted laparoscopic (RAL) surgery. MATERIALS AND METHODS: Thermal spread along bovine musculofascial tissues was examined by infrared camera, histology and enzyme assay. Currently used monopolar, bipolar and ultrasonic laparoscopic instruments were investigated at various power settings and application times. The efficacy of using an additional Maryland clamp as a heat sink was evaluated. A temperature of 45 °C was considered the threshold temperature for possible nerve damage. RESULTS: Monopolar instruments exhibited a mean (sem) critical thermal spread of 3.5 (2.3) mm when applied at 60 W for 1 s. After 2 s, the spread was >20 mm. For adjustable bipolar instruments the mean (sem) critical thermal spread was 2.2 (0.6) mm at 60 W and 1 s, and 3.6 (1.3) mm at 2 s. The PK and LigaSure forceps had mean (sem) critical thermal spreads of 3.9 (0.8) and 2.8 (0.6) mm respectively, whereas the ultrasonic instrument reached 2.9 (0.8) mm. Application of an additional Maryland clamp as a heat sink, significantly reduced the thermal spread. Histomorphometric analyses and enzyme assay supported these findings. CONCLUSIONS: All coagulation devices used in RAL surgery have distinct thermal spreads depending on power setting and application time. Cautery may be of concern due to lateral temperature spread, causing potential damage to sensitive structures including nerves. Our results provide surgeons with a resource for educated decision-making when using coagulation devices during robotic procedures.

Subglotic malt-lymphoma of the larynx: an unusual presentation of chronic cough.

Extranodal non-Hodgkin lymphomas limited to the larynx are rare, accounting for less than 1% of all laryngeal neoplasms. The most common site of development of primary laryngeal lymphomas is the supraglottic region. In most cases, the presenting symptoms are hoarseness, dysphagia, dyspnea, and cervical lymphadenopathy. They consist mainly of non-Hodgkin lymphoma, especially of diffuse large B-cell lymphoma and mucosa-associated lymphoid tissue. We report a case of a primary extranodal marginal zone of mucosa-associated lymphoid tissue (Malt Lymphoma) of the larynx in a 73-year-old non-smoker woman, presented as chronic cough, unresponsive to oral corticosteroid. We present a detailed report of her clinical and paraclinical data as well as treatment options. In patients with chronic cough, uncommon causes should be considered when the cough persists after evaluation for common causes. If a cough persists after consideration of the most common causes, CT scan and a bronchoscopic evaluation are fundamental for the diagnosis of tumors of the upper and lower respiratory tract.

Bilaterally positive biopsy cores are associated with non-organ-confined disease in prostate cancer patients eligible for active surveillance.

PURPOSE: To investigate the association between the laterality of diagnostic prostate cancer-positive biopsy cores and definitive tumor stage on final pathology (organ-confined versus non-organ-confined). PATIENTS AND METHODS: This is a retrospective analysis of 165 men after radical prostatectomy fulfilling our active surveillance criteria at the time of surgery. Nominal variables were compared using Fisher's exact test, continuous variables using Mann-Whitney test. Odds ratios including 95% Wald and probabilities including 95% Wilson confidence intervals are provided. RESULTS: 5 (3%) patients had non-organ-confined disease: 2 out of 144 (1%) patients with unilateral and 3 out of 17 (18%) patients with bilateral cancer-positive biopsy cores (p = 0.009). The estimated odds ratio for non-organ-confined disease was 14.67 (95% confidence interval 1.55-189.23) for patients with bilateral compared to patients with unilateral cancer-positive biopsy cores. The sensitivity, specificity and accuracy of bilaterally positive biopsies as an additional criterion to identify non-organ-confined disease are 60, 91 and 90%, respectively. CONCLUSION: In our cohort, patients with bilaterally positive biopsy cores were significantly more likely to harbor a non-organ-confined tumor than patients with unilaterally positive cores. Due to their high specificity, bilaterally positive biopsies may represent a reasonable exclusion criterion for active surveillance if our results are corroborated in further studies.

Influence of tinnitus annoyance on hearing-related quality of life in cochlear implant recipients.

Tinnitus is a common symptom in cochlear implant (CI) recipients. There is no clear evidence of the influence of tinnitus on hearing-related quality of life (QoL) in this population. The aim of this study was to assess the relationship between hearing-related QoL measured by the Speech, Spatial and Qualities of Hearing scale (SSQ12) and tinnitus annoyance or perceived change in tinnitus annoyance after cochlear implantation. The study sample consisted of 2322 implanted adults across France, Germany, Ireland, Italy, the Netherlands, Sweden and the United Kingdom. Information relating to QoL measured using the SSQ12 and tinnitus annoyance and change in tinnitus annoyance, assessed using single-item questions, were collected one or more years post-implantation. The relationship between SSQ12 score and tinnitus annoyance or change in tinnitus annoyance was analysed using linear models adjusted for age and unilateral versus bilateral implants. Tukey pairwise tests were used to compare mean SSQ12 scores across levels of tinnitus annoyance and changes. Tinnitus prevalence was 33.9% post-implantation. Recipients with tinnitus had a significantly lower SSQ12 score than recipients without tinnitus. SSQ scores varied significantly with tinnitus annoyance, age and unilateral versus bilateral implants. Overall, CI recipients who experienced less bothersome tinnitus reported better hearing-related QoL. Healthcare professionals should be aware of the influence of tinnitus on CI recipients' hearing to manage patient expectations.

Wnt (canonical and non canonical) pathways in breast carcinoma with extensive vascular invasion and inflammatory breast carcinoma.

BACKGROUND: Breast carcinoma with extensive peritumoral vascular invasion (ePVI-BC) is a cancer with massive vascular invasion (>10) detected in more than one slide. This neoplasm shows clinic-pathological affinity with inflammatory breast carcinoma (IBC). In this paper we evaluate their biological relationship through the study of surrogate markers (ß-catenin and NFAT5) of Canonical (cWnt) and non-canonical (nWnt) Wnt pathways activation. METHODS: By immunoistochemistry, we investigate ß-catenin and NFAT5 in 39 IBC, 74 ePVI-BC and 84 control cases (CG-BC). RESULTS: cWnt was activated in 100 % of ePVI-BC, in 64 % of IBC and 10 % of CG-BC. nWnt was activated in 20 % of ePVI-BC, 50 % of IBC and 1% of CG-BC. The prognosis of carcinomas with nWnt activated was poor similar to IBC. The statistical analysis evidences as both the pathways are synergistic in malignant progression and survival time. ß-catenin show an important association with prognostic factors and NFAT5 shows a relevant prognostic role on OS (p = 1.5*10-6) and DFS (P = 1,2*10-4). nWnt is associated with a worse prognosis independently of cWnt. cWnt is associated with adverse prognosis (DFS p = 0.0469; OS p = 0.004891) but its prognostic role is indifferent in carcinoma with nWnt activated. CONCLUSIONS: Canonical Wnt pathway is involved in malignant progression with dominant role for vascular invasion whereas non canonical Wnt pathway plays an important role on survival time including the capacity to identify carcinomas with IBC-like prognosis. Furthermore ePVI may represent a "prodromal form of IBC" as demonstrated by its clinicopathological and biological similarity with IBC.

Uterine PEComa with aggressive behavior: A review with an additional case of spontaneous vaginal expulsion.

Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal tumor originating from perivascular epitheloid cells showing melanocytic and smooth muscle differentiation. The uterus represents the second most common site of origin. A 49 years woman presented to our Hospital for a vaginal spontaneous expulsion of a mass suggestive for malignant mesenchymal tumor. The patient underwent total hysterectomy and bilateral salpingo-oophorectomy and the histopathological report was compliant with a PEComa with aggressive behavior. Medical Literature databases about PEComa were searched. The current literature identified near 90 cases of uterine PEComas and they are categorized as uncertain malignant potential or with aggressive behavior. Primary surgical excision represents the gold-standard treatment. Recently targeted therapy with mTOR inhibitors has been introduced with an important beneficial. In this paper we review the Literature about the uPEComa with aggressive behavior reporting the first case of spontaneous vaginal expulsion.

Characterization of dose-dependent Young's modulus for a radiation-sensitive polymer gel.

Radiation-sensitive polymer gels for clinical dosimetry have been intensively investigated with magnetic resonance imaging (MRI) because the transversal magnetic relaxation time is dependent on irradiation dose. MRI is expensive and not easily available in most clinics. For this reason, low-cost, quick and easy-to-use potential alternatives such as optical computed tomography (CT), x-ray CT or ultrasound attenuation CT have also been studied by others. Here, we instead evaluate the dose dependence of the elastic material property, Young's modulus and the dose response of the viscous relaxation of radiation-sensitive gels to discuss their potential for dose imaging. Three batches of a radiation-sensitive polymer gel (MAGIC gel) samples were homogeneously irradiated to doses from 0 Gy to 45.5 Gy. Young's modulus was computed from the measured stress on the sample surface and the strain applied to the sample when compressing it axially, and the viscous relaxation was determined from the stress decay under sustained compression. The viscous relaxation was found not to change significantly with dose. However, Young's modulus was dose dependent; it approximately doubled in the gels between 0 Gy and 20 Gy. By fitting a second-order polynomial to the Young's modulus-versus-dose data, 99.4% of the variance in Young's modulus was shown to be associated with the change in dose. The precision of the gel production, irradiation and Young's modulus measurement combined was found to be 4% at 2 Gy and 3% at 20 Gy. Potential sources of measurement error, such as those associated with the boundary conditions in the compression measurement, inhomogeneous polymerization, temperature (up to 1% error) and the evaporation of water from the sample (up to 1% error), were estimated and discussed. It was concluded that Young's modulus could be used for dose determination. Imaging techniques such as elastography may help to achieve this if they can provide a local measurement of Young's modulus, which may eliminate problems associated with the boundaries (e.g. variation in coefficient of friction) and inhomogeneous polymerization. Elastography combined with a calibration should also be capable of mapping dose in three dimensions.

ZAP-70 expression, as detected by immunohistochemistry on bone marrow biopsies from early-phase CLL patients, is a strong adverse prognostic factor.

Zeta-associated protein-70 (ZAP-70), mostly assessed by flow-cytometry (FC), recently emerged as reliable prognostic factor in chronic lymphocytic leukaemia (CLL) at presentation. We evaluated ZAP-70 expression in 156 CLL patients by immunohistochemistry (IHC) on formalin-fixed bone marrow (BM) biopsies at diagnosis. At presentation, 117 patients (75%) were with Binet stage A, 27 (17%) stage B and 12 (8%) stage C. Median follow-up was 61 months (range 6-242). ZAP-70 was expressed in neoplastic lymphocytes of 69 patients (44%). Concordance between ZAP-70 by IHC and ZAP-70 by FC, immunoglobulin heavy chain variable genes (IGHV) mutational status and CD38 expression was found in 41/46 (89%), 41/49 (80%) and in 60/88 (68%) tested cases, respectively. ZAP-70 expression significantly correlated with advanced Binet stage (B-C), diffuse BM infiltration, increased lactate dehydrogenase (LDH) and beta2-microglobulin serum levels and lymphocyte doubling time <12 months. ZAP-70 positivity was significantly related to poorer time to progression (median 16 months vs 158 of ZAP-70-negative cases) (P<0.0001) and overall survival (median 106 months vs not reached) (P=0.0002); this correlation was confirmed at multivariate analysis. ZAP-70 expression correlated with poorer outcome also when evaluated only in the 117 stage A patients. In conclusion, immunohistological detection of ZAP-70 on formalin-fixed BM biopsies at diagnosis appears a useful methodological approach to identify patients with poor prognosis in CLL.

Patient Acceptance of Invasive Treatments for Tinnitus.

PURPOSE: The field of neuromodulation is currently seeking to treat a wide range of disorders with various types of invasive devices. In recent years, several preclinical trials and case reports in humans have been published on their potential for chronic tinnitus. However, studies to obtain insight into patients' willingness to undergo these treatments are scarce. The aim of this survey study was to find out whether tinnitus patients are willing to undergo invasive neuromodulation when taking its risks, costs, and potential benefits into account. METHOD: A Visual Analog Scale (VAS, 0-10) was used to measure the outcome. Spearman's rank-order correlation coefficients were computed to determine the correlation between patient characteristics and acceptance rates. RESULTS: Around one fifth of the patients were reasonably willing to undergo invasive treatment (VAS 5-7), and around one fifth were fully willing to do so (VAS 8-10). Hearing aids, used as a control, were accepted most, followed by cochlear implantation, deep brain stimulation, and cortical stimulation. Acceptance rates were slightly higher when the chance of cure was higher. Patients with a history of attempted treatments were more eager than others to find a new treatment for tinnitus. CONCLUSIONS: A considerable proportion of patients with tinnitus would accept a variety of invasive treatments despite the associated risks or costs. When clinical neuromodulatory studies for tinnitus are to be performed, particular attention should be given to obtaining informed consent, including explaining the potential risks and providing a realistic outcome expectation.

Introducing gel dosimetry in a clinical environment: customization of polymer gel composition and magnetic resonance imaging parameters used for 3D dose verifications in radiosurgery and intensity modulated radiotherapy.

Radiation sensitive gels have been used as dosimeters for clinical dose verification of different radiation therapy modalities. However, the use of gels is not widespread, because careful techniques are required to achieve the dose precision and accuracy aimed for in clinical dose verification. Here, the introduction of gel dosimetry in a clinical environment is described, including the whole chain of customizations and preparations required to introduce magnetic resonance (MR) based gel dosimetry into clinical routine. In order to standardize gel dosimetry in dose verifications for radiosurgery and intensity modulated radiotherapy (IMRT), we focused on both the customization of the gel composition and of the MR imaging parameters to increase its precision. The relative amount of the components of the normoxic, methacrylic acid based gel (MAGIC) was changed to obtain linear and steep dose response relationships. MR imaging parameters were customized for the different dose ranges used in order to lower the relative standard deviation of the measured transversal relaxation rate (R2). An optimization parameter was introduced to quantify the change in the relative standard deviation of R2 (sigma(R2,rel)) taking the increase in MR time into account. A 9% methacrylic acid gel customized for radiosurgery was found to give a linear dose response up to 40 Gy with a slope of 0.94 Gy(-1) s(-1), while a 6% methacrylic acid gel customized for IMRT had a linear range up to 3 Gy with a slope of 1.86 Gy(-1) s(-1). With the help of an introduced optimization parameter, the mean sigma(R2,rel) was improved by 13% for high doses and by 55% for low doses, without increasing MR time to unacceptable values. A mean dose resolution of less than 0.13 Gy has been achieved with the gel and imaging parameters customized for IMRT and a dose resolution from 0.97 Gy (at 5 Gy) to 2.15 Gy (at 40 Gy) for the radiosurgery dose range. The comparisons of calculated and measured relative 3D dose distributions performed for radiosurgery and IMRT showed an acceptable overall correlation. The gamma criterion for the radiosurgery verification with a voxel size of 1.5 x 1.5 x 1.5 mm3 was passed by 96.8% of the voxels (1.5 mm distance, 8% in dose). For the IMRT verification using a voxel size of 1.25 x 1.25 x 5 mm3 the gamma criterion was passed by 50.3% of the voxels (3 mm distance, 3% dose uncertainty). Using dedicated data analysis and visualization software, MR based normoxic gel dosimetry was found to be a valuable tool for clinically based dose verification, provided that customized gel compositions and MR imaging parameters are used. While high dose precision was achieved, further work is required to achieve clinically acceptable dose accuracy.

Characterization of the ultrasonic attenuation coefficient and its frequency dependence in a polymer gel dosimeter.

Research on polymer-gel dosimetry has been driven by the need for three-dimensional dosimetry, and because alternative dosimeters are unsatisfactory or too slow for that task. Magnetic resonance tomography is currently the most well-developed technique for determining radiation-induced changes in polymer structure, but quick low-cost alternatives remain of significant interest. In previous work, ultrasound attenuation and speed of sound were found to change as a function of absorbed radiation dose in polymer-gel dosimeters, although the investigations were restricted to one ultrasound frequency. Here, the ultrasound attenuation coefficient mu in one polymer gel (MAGIC) was investigated as a function of radiation dose D and as a function of ultrasonic frequency f in a frequency range relevant for imaging dose distributions. The nonlinearity of the frequency dependence was characterized, fitting a power-law model mu = af(b); the fitting parameters were examined for potential use as additional dose readout parameters. In the observed relationship between the attenuation coefficient and dose, the slopes in a quasi-linear dose range from 0 to 30 Gy were found to vary with the gel batch but lie between 0.0222 and 0.0348 dB cm(-1) Gy(-1) at 2.3 MHz, between 0.0447 and 0.0608 dB cm(-1) Gy(-1) at 4.1 MHz and between 0.0663 and 0.0880 dB cm(-1) Gy(-1) at 6.0 MHz. The mean standard deviation of the slope for all samples and frequencies was 15.8%. The slope was greater at higher frequencies, but so were the intra-batch fluctuations and intra-sample standard deviations. Further investigations are required to overcome the observed variability, which was largely associated with the sample preparation technique, before it can be determined whether any frequency is superior to others in terms of accuracy and precision in dose determination. Nevertheless, lower frequencies will allow measurements through larger samples. The fit parameter a of the frequency dependence, describing the attenuation coefficient at 1 MHz, was found to be dose dependent, which is consistent with our expectations, as polymerization is known to be associated with increased absorption of ultrasound. No significant dose dependence was found for the fit parameter b, which describes the nonlinearity with frequency. This is consistent with the increased absorption being due to the introduction of new relaxation processes with characteristic frequencies similar to those of existing processes. The data presented here will help with optimizing the design of future 3D dose-imaging systems using ultrasound methods.

Polyclonal antibodies for the detection of Trypanosoma cruzi circulating antigens.

BACKGROUND: Detection of Trypanosoma cruzi antigens in clinical samples is considered an important diagnostic tool for Chagas disease. The production and use of polyclonal antibodies may contribute to an increase in the sensitivity of immunodiagnosis of Chagas disease. METHODOLOGY/PRINCIPAL FINDINGS: Polyclonal antibodies were raised in alpacas, rabbits, and hens immunized with trypomastigote excreted-secreted antigen, membrane proteins, trypomastigote lysate antigen and recombinant 1F8 to produce polyclonal antibodies. Western blot analysis was performed to determine specificity of the developed antibodies. An antigen capture ELISA of circulating antigens in serum, plasma and urine samples was developed using IgY polyclonal antibodies against T. cruzi membrane antigens (capture antibody) and IgG from alpaca raised against TESA. A total of 33 serum, 23 plasma and 9 urine samples were analyzed using the developed test. Among serum samples, compared to serology, the antigen capture ELISA tested positive in 55% of samples. All plasma samples from serology positive subjects were positive in the antigen capture ELISA. All urine positive samples had corresponding plasma samples that were also positive when tested by the antigen capture ELISA. CONCLUSIONS: Polyclonal antibodies are useful for detection of circulating antigens in both the plasma and urine of infected individuals. Detection of antigens is direct evidence of the presence of the parasite, and could be a better surrogate of current infection status.

Immunohistochemical evaluation of mismatch repair proteins in colorectal carcinoma: the AIFEG/GIPAD proposal.

Microsatellite instability (MSI) is a hypermutable phenotype that usually arises from either a germline mutation in components of the mismatch repair (MMR) machinery (i.e. hMLH1, MSH2, MSH6 and PMS2) in patients with Lynch syndrome (LS) or somatic hypermethylation of the hMLH1 promoter in sporadic carcinomas. In all colorectal cancers (CRC) is possible to identify the MMR deficiency through protein expression by immunoistochemistry (IHC). Recently, the predictive role of MMR deficiency in reduced chemotherapy benefit and the introduction of universal screening for Lynch syndrome suggest to include MMR testing into routine clinical practice. In this scenario is mandatory to update the minimal requirements for MMR IHC standardization and evaluation. According to international guidelines, these are the GIPAD and AIFEG suggestions for MMR IHC testing.

Long-term effects of intracochlear electrical stimulation with looped patterns on tinnitus: A case study.

Electrical stimulation by cochlear implant (CI) has been proven to be a viable treatment option for tinnitus in many recent studies. In addition, intracochlear electrical stimulation independent of an acoustic input appears to suppress tinnitus, at least in the short term. We conducted a case study to investigate the long-term effects of both standard CI and intracochlear electrical stimulation independent of an acoustic input on tinnitus in a patient with single-sided deafness and tinnitus. We found no negative effects of intracochlear electrical stimulation independent of an acoustic input on speech perception in noise. Furthermore, the additional use of a standard CI was advantageous for speech discrimination in our patient. We conclude that long-term tinnitus suppression can be achieved via intracochlear electrical stimulation with looped patterns. Our findings in terms of speech discrimination in our patient were consistent with those reported in previous studies.

Tinnitus Suppression by Intracochlear Electrical Stimulation in Single Sided Deafness - A Prospective Clinical Trial: Follow-Up.

INTRODUCTION: Earlier studies show that a Cochlear Implant (CI), capable of providing intracochlear electrical stimulation independent of environmental sounds, appears to suppress tinnitus at least for minutes. The current main objective is to compare the long-term suppressive effects of looped (i.e. repeated) electrical stimulation (without environmental sound perception) with the standard stimulation pattern of a CI (with environmental sound perception). This could open new possibilities for the development of a "Tinnitus Implant" (TI), an intracochlear pulse generator for the suppression of tinnitus. MATERIALS AND METHODS: Ten patients with single sided deafness suffering from unilateral tinnitus in the deaf ear are fitted with a CI (MED-EL Corporation, Innsbruck, Austria). Stimulation patterns are optimized for each individual patient, after which they are compared using a randomized crossover design, with a follow-up of six months, followed by a 3 month period using the modality of patient's choice. RESULTS: Results show that tinnitus can be suppressed with intracochlear electrical stimulation independent of environmental sounds, even long term. No significant difference in tinnitus suppression was found between the standard clinical CI and the TI. CONCLUSION: It can be concluded that coding of environmental sounds is no requirement for tinnitus suppression with intracochlear electrical stimulation. It is therefore plausible that tinnitus suppression by CI is not solely caused by an attention shift from the tinnitus to environmental sounds. Both the standard clinical CI and the experimental TI are potential treatment options for tinnitus. These findings offer perspectives for a successful clinical application of the TI, possibly even in patients with significant residual hearing. TRIAL REGISTRATION: TrialRegister.nl NTR3374.