Treatment of snoring using a non-invasive Er:YAG laser with SMOOTH mode (NightLase): a randomized controlled trial.

OBJECTIVES: The aim of this study was to assess safety and efficacy of a non-invasive 2940 nm Er:YAG treatment with SMOOTH mode in reducing snoring in adult patients and to compare its efficacy and safety to sham treatment in a randomized controlled trial setting.  METHODS: 40 primary snoring patients (≥ 18 year, AHI < 15e/h, BMI ≤ 30) were randomized to receive either 3 sessions NightLase or sham laser treatment. The main outcome measures were Snore Outcomes Survey (SOS), the Spouse/Bed Partner Survey (SBPS), a visual analogue snoring scale (bed partner) and a visual analogue pain scale. RESULTS: NightLase was well tolerated, no local anaesthesia was required (mean VAS pain score in NightLase group = 3.0 ± 1.7). No complications occurred. SOS, SBPS and VAS snoring scores improved in the NightLase group (33.7 ± 14.1 to 56.2 ± 16.1) (35.0 ± 17.1 to 61.5 ± 16.4) and (7.9 ± 2.0 to 4.7 ± 2.8) while no changing in the sham group (32.2 ± 14.5 vs 32.1 ± 13.0) (36.7 ± 12.1 vs 34.7 ± 12.7) (8.1 ± 1.7 vs 8.0 ± 1.6), respectively. CONCLUSIONS: NightLase is a safe, minimal invasive treatment that significantly reduced snoring compared to sham treatment.

Impulse Configuration in Hypoglossal Nerve Stimulation in Obstructive Sleep Apnea: The Effect of Modifying Pulse Width and Frequency.

OBJECTIVES: Hypoglossal nerve stimulation is an effective treatment option for obstructive sleep apnea (OSA) in positive airway pressure therapy failure. Nonetheless, data regarding the functional effect of modifying stimulation parameters within each electrode configuration are limited. MATERIALS AND METHODS: In a retrospective study of 76 patients with 12 months or more follow-up, functional tongue protrusion thresholds were compared for pulse width and frequency configurations of 90 µsec 33 Hz vs 120 µsec 40 Hz. The number of tolerated voltage amplitude steps between sensation, functional, and subdiscomfort thresholds were assessed for both settings as well as impedances. RESULTS: The overall cohort showed improvement in OSA metrics: median apnea-hypopnea index from 30.0/hour to 18.6/hour and Epworth Sleepiness Scale from 13.5 to 7.6. For both bipolar and unipolar electrode configurations, the stimulation amplitude required for functional tongue protrusion was significantly reduced when the pulse width and frequency were converted from 90 µsec 33 Hz to 120 µsec 40 Hz (p < 0.001). Nevertheless, the number of voltage amplitude steps from sensation, functional, to subdiscomfort thresholds did not differ between the two settings. The ratio of automatically derived impedances between bipolar and unipolar electrode configurations was relevantly correlated with the ratio of functional thresholds at these parameters. CONCLUSION: Changing the stimulation parameters may lower the voltage requirements while maintaining the same effect on tongue protrusion. Changing these stimulation parameters does not affect the range of tolerated impulse steps between functional and subdiscomfort thresholds. Future technical appliances could help estimate functional thresholds at different electrode configurations for each patient by automatically measuring impedances.

Upper airway stimulation in obstructive sleep apnea improves glucose metabolism and reduces hedonic drive for food.

Upper airway stimulation is a new and effective second-line treatment for obstructive sleep apnea, but possible consequences on glucose metabolism and central regulation of food intake are unclear. Twenty patients were prospectively studied before and 12 months after obstructive sleep apnea treatment by upper airway stimulation. Respiratory parameters and daytime sleepiness were assessed to document effectiveness of treatment. Glucose metabolism was assessed by the oral glucose tolerance test, and hedonic versus homeostatic drive to eat was characterized. At 12 months, upper airway stimulation significantly improved measures of obstructive sleep apnea (all p < 0.01). Despite no change in body weight, fasting C-peptide insulin resistance index (p = 0.01) as well as insulin and C-peptide levels at 60 min during the oral glucose tolerance test (p < 0.02) were reduced. Hedonic drive to eat was strongly reduced (p < 0.05), while leptin and ghrelin remained unchanged (p > 0.15). Upper airway stimulation is effective in treatment of obstructive sleep apnea and improves glucose metabolism. Reduced hedonic drive to eat might contribute to these metabolic improvements. These promising findings are in need for long-term controlled evaluation of metabolic sequelae of upper airway stimulation and to mechanistically evaluate the metabolic benefits of upper airway stimulation in patients with obstructive sleep apnea.

Patient experience with upper airway stimulation in the treatment of obstructive sleep apnea.

OBJECTIVE: Selective upper airway stimulation (sUAS) is a new treatment modality for patients with obstructive sleep apnea (OSA) and continuous positive airway pressure (CPAP) failure. The aim of this study was to analyze therapy adherence and to structure patient experience reports. METHODS: Patients from two German implantation centers were included. Besides demographic and OSA characteristics of that cohort, patients answered a questionnaire on subjective sensation of the stimulation, use of different functions, side effects, and an inventory for the description of the attitude towards sUAS. The use of the sUAS was evaluated as a read-out of the implanted system. RESULTS: The overall apnea-hypopnea-index (AHI) of that 102 assessed patients reduced from initially 32.8/h to 12.6/h at the last available assessment. The responder rate was 75%. There was an objective therapy usage of 5.7 h and subjective reports of 6.8 nights per week. The attitude resulted in strong agreement towards the statement "UAS reduces the problems caused by my sleep apnea". Information on sensing the stimulation and usage habits could be gathered such as that stimulation is only sensed by 67.9% of the patients upon waking in the morning and that 73.6% of the patients do not change the voltage in general. CONCLUSION: This investigation on the sUAS therapy revealed a high adherence to the therapy. The AHI or daytime sleepiness do not have obvious influence on adherence. Patients expressed a positive attitude towards sUAS. These patient reports upon stimulation experiences are of great help to consult candidates for sUAS in future.

In situ detection of PR3-ANCA+ B cells and alterations in the variable region of immunoglobulin genes support a role of inflamed tissue in the emergence of auto-reactivity in granulomatosis with polyangiitis.

Circulating anti-neutrophilic cytoplasmic autoantibodies targeting proteinase 3 (PR3-ANCA) are a diagnostic and pathogenic hallmark of granulomatosis with polyangiitis (GPA). It is, however, incompletely understood if inflamed tissue supports presence or emergence of PR3-ANCA+ B cells. In search of such cells in inflamed tissue of GPA, immunofluorescence staining for IgG and a common PR3-ANCA idiotype (5/7 Id) was undertaken. Few 5/7 Id+/IgG+ B cells were detected in respiratory and kidney tissue of GPA. To gain more insight into surrogate markers possibly indicative of an anti-PR3-response, a meta-analysis comprising IGVH and IGVL genes derived from respiratory tract tissue of GPA (231 clones) was performed. Next generation sequencing-based IGHV genes derived from peripheral blood of healthy donors (244.353 clones) and previously published IGLV genes (148 clones) served as controls. Additionally, Ig genes of three murine and five known human monoclonal anti-PR3 antibodies were analyzed. Primary and probably secondary rearrangements led to altered VDJ usage and an extended complementarity determining region 3 (CDR3) of IGHV clones from GPA tissue. Selection against amino acid exchanges was prominent in the framework region of IGHV clones from GPA tissue. The comparison of V(D)J rearrangements and deduced amino acid sequences of the CDR3 yielded no identities and few similarities between clones derived from respiratory tissue of GPA and anti-PR3 antibodies, arguing against a presence of B cells that carry PR3-ANCA-prone Ig genes among the clones. In line with the scarcity of 5/7 Id+ B lymphocytes in GPA tissue, the results suggest that with respect to a local anti-PR3 response, methods detecting rare clones are required.

Complete concentric collapse at the soft palate in sleep endoscopy: what change is possible after UPPP in patients with CPAP failure?

PURPOSE: The aim of this work was to assess whether uvulopalatopharyngoplasty in patients with failure for positive airway pressure not only reduces the degree of obstructive sleep apnea but also to determine as well if it changes the collapse pattern of the soft palate and thereby fulfills the qualifications for implementing upper airway stimulation (UAS) as an adjunctive solution. METHOD: Fifteen patients with intolerance for positive airway pressure were included in this retrospective cohort study. Polygraphy and drug-induced sleep endoscopy were used in order to evaluate the reduction of the apnea-hypopnea index (AHI), as well as the change of collapse pattern at the soft palate level before and about 3 months after uvulopalatopharyngoplasty and tonsillectomy (TE-UPPP). RESULTS: In 93% of the patients, a postoperative change of the initially complete concentric palatal collapse pattern could be found during drug-induced sleep endoscopy. In one patient, no obstruction at all was seen at the soft palatal level. Only one patient still presented with a complete concentric collapse at velum level. AHI decreased from mean 34.7 events per hour to 20.2/h and oxygen desaturation index from 25.3 events per hour to 16.1/h. CONCLUSION: Patients seeking for positive airway pressure alternatives could not only benefit from reduction of AHI by TE-UPPP postoperatively; additionally, by changing the collapse pattern at the soft palate, they might also fulfill criteria for upper airway stimulation (UAS) in case of persistent OSA of at least moderate degree.

Patient-reported outcome: results of the multicenter German post-market study.

PURPOSE: Upper airway stimulation (UAS) is an alternative second-line treatment option for patients with obstructive sleep apnea (OSA). In our substudy of a previous multicentre study of patients implanted with UAS, we focused on patient-related outcomes like Epworth Sleepiness Scale (ESS), the Functional Outcomes of Sleep Questionnaire (FOSQ), snoring and personal satisfaction 6 and 12 months after the implantation. METHODS: 60 patients, who were initially non-adherent to CPAP and implanted with UAS, were included in a prospective multicentre study. Data were collected preoperative, 6 and 12 months after implantation regarding FOSQ, ESS, snoring, and their experience with the UAS device. RESULTS: Besides relevant Apnoea-Hypopnea Index (AHI) reduction, we saw significant improvements in ESS (p < 0.001), FOSQ (p < 0.001) and snoring under UAS therapy. A strong correlation between AHI results postoperative and the personal satisfaction of the patients after implantation was found as well as between usage results and AHI compared to the preoperative results. CONCLUSION: The more the patients benefit from UAS according to their self-reported outcome, the higher is the therapy use.

Nuclear expression of p65 (RelA) in patients receiving post-operative radiotherapy for locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: This study investigated the prognostic role of nuclear expression of p65 in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) receiving post-operative radio(chemo)therapy. METHODS: Nuclear p65-expression (H-score ≤50 versus >50) plus twelve characteristics were analyzed in 151 patients for overall survival (OS), metastases-free survival (MFS) and loco-regional control (LRC). Additional characteristics included age, gender, Karnofsky performance score (KPS), pre-radiotherapy hemoglobin levels, tumor site, histological grading, human papilloma virus (HPV)-status, T-classification, N-classification, American Joint Committee on Cancer (AJCC)-stage, extent of resection and concurrent chemotherapy. Univariate analyses were performed with Kaplan-Meier method and log-rank test, multivariate analyses with Cox proportional hazards model. RESULTS: On univariate analyses, p65-expression had a significant impact on OS (p < 0.001) and LRC (p < 0.001) but not on MFS (p = 0.29). On multivariate analysis, KPS ≥80 (risk ratio [RR] 2.23; p = 0.012), HPV-positivity (RR 5.83; p = 0.020), T1-T2 (RR 1.38; p = 0.048), N0-N2a (RR 2.72; p = 0.005) and complete resection (RR 2.02; p = 0.049) were positively associated with OS; p65-negativity achieved borderline significance (RR 3.02; p = 0.052). Better MFS was associated with KPS ≥80 (RR 2.49; p = 0.015), T1-T2 (RR: 1.74; p = 0.005), N0-N2a (RR: 6.22; p < 0.001) and complete resection (RR 3.43; p = 0.003). Positive associations with LRC were found for p65-negativity (RR 5.06; p = 0.008), T1-T2 (RR: 1.49; p = 0.022), N0-N2a (RR: 2.97; p = 0.004) and favorable tumor site (RR 1.28; p = 0.025). CONCLUSIONS: P65-negativity was significantly associated with improved LRC and achieved borderline significance with respect to improved OS. Thus, p65-expression may be an additional target for novel agents in the treatment of locally advanced SCCHN.

Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible.

Nephrotic syndrome, a malfunction of the kidney glomerular filter, leads to proteinuria, edema and, in steroid-resistant nephrotic syndrome, end-stage kidney disease. Using positional cloning, we identified mutations in the phospholipase C epsilon gene (PLCE1) as causing early-onset nephrotic syndrome with end-stage kidney disease. Kidney histology of affected individuals showed diffuse mesangial sclerosis (DMS). Using immunofluorescence, we found PLCepsilon1 expression in developing and mature glomerular podocytes and showed that DMS represents an arrest of normal glomerular development. We identified IQ motif-containing GTPase-activating protein 1 as a new interaction partner of PLCepsilon1. Two siblings with a missense mutation in an exon encoding the PLCepsilon1 catalytic domain showed histology characteristic of focal segmental glomerulosclerosis. Notably, two other affected individuals responded to therapy, making this the first report of a molecular cause of nephrotic syndrome that may resolve after therapy. These findings, together with the zebrafish model of human nephrotic syndrome generated by plce1 knockdown, open new inroads into pathophysiology and treatment mechanisms of nephrotic syndrome.

Evaluation of the prognostic role of tumor cell podoplanin expression in locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND AND PURPOSE: To investigate the potential prognostic role of tumor cell podoplanin expression in patients treated with resection followed by irradiation or chemoradiotherapy for locally advanced squamous cell carcinoma of the head and neck (SCCHN). MATERIALS AND METHODS: Podoplanin expression (≤10 % versus > 10 %) and 12 other factors were evaluated in 160 patients for their association with locoregional control (LRC), metastases-free (MFS) and overall survival (OS). Other factors were age, gender, Eastern Cooperative Oncology Group (ECOG) performance status, preradiotherapy (pre-RT) hemoglobin level, tumor site, histological grading, T category, N category, American Joint Committee on Cancer (AJCC) stage, human papillomavirus (HPV) status, extent of resection and concurrent chemotherapy. RESULTS: In multivariate analysis, ECOG performance status 0-1 (risk ratio, RR: 3.01; 95 % confidence interval, CI: 1.42-7.14; p = 0.003), pre-RT hemoglobin levels ≥ 7.45 mmol/l (12 g/dl; RR: 2.03; 95 % CI: 1.04-3.94; p = 0.038), oropharyngeal cancer (RR: 1.25; 95 % CI: 1.01-1.55; p = 0.038) and T category T1-2 (RR: 1.81; 95 % CI: 1.24-2.79; p = 0.002) were significantly associated with improved LRC. T category T1-2 (RR: 1.90; 95 % CI: 1.25-3.06; p = 0.002) and N category N0-2a (RR: 5.22; 95 % CI: 1.96-18.09; p < 0.001) were significantly associated with better MFS. Pre-RT hemoglobin levels ≥ 7.45 mmol/l (RR: 2.44; 95 % CI: 1.27-4.74; p = 0.007), T category T1-2 (RR: 1.97; 95 % CI: 1.36-3.04; p < 0.001) and N category N0-2a (RR: 2.87; 95 % CI: 1.37-6.61; p = 0.005) were significantly associated with improved OS. Podoplanin expression ≤ 10 % showed a trend towards improved OS on both univariate (p = 0.050) and multivariate analysis (RR: 1.86; 95 % CI: 0.96-3.59; p = 0.07). CONCLUSION: Treatment outcomes were significantly associated with performance status, pre-RT hemoglobin level, tumor site and tumor stage. Tumor cell expression of podoplanin ≤ 10 % showed a trend towards improved OS when compared to podoplanin expression of > 10 %.

Home Sleep Testing to Direct Upper Airway Stimulation Therapy Optimization for Sleep Apnea.

OBJECTIVES/HYPOTHESIS: Selective upper airway stimulation (sUAS) is a well-established treatment option for obstructive sleep apnea (OSA). This study aimed to determine if there are benefits in performing a home sleep test (HST) to evaluate postoperative sUAS effectiveness after patient acclimatization compared to the generally used polysomnography (PSG) titration, as measured by long-term follow-up outcomes. STUDY DESIGN: Retrospective comparative cohort analysis. METHODS: We conducted an analysis of consecutive patients at our center who had completed a 6-month follow-up (month 6 [M6]) and recorded data from M6, month 12 (M12), and month 24 (M24). After device activation, we performed an HST with the patient's stimulation settings, and measured the apnea-hypopnea index (AHI), Epworth Sleepiness Scale (ESS), and device usage. These values were compared to patients who had undergone PSG-based device titration. RESULTS: Baseline values of the initial 131 patients show high ESS and moderate OSA. At the 2-month time point of the HST, nearly half of the patients (46.2%) reached an AHI ≤15/hr, and approximately a fifth (19.2%) reached <5/hr. The PSG and HST groups differed in median ESS at M24, but no other differences were observed for ESS at M6 and M12. Both groups showed similar AHI, oxygen desaturation, and usage hours per week. CONCLUSIONS: Adjusting therapy by using the HST technique after device activation and acclimatization has clinical and economic advantages. These advantages are contingent on several conditions being met when deviating from the standard device protocol, including precise communication with the referring sleep medicine physicians, especially their role in helping with long-term follow-up. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E1375-E1379, 2021.

Changes in breath cycle sensing affect outcomes in upper airway stimulation in sleep apnea.

BACKGROUND: Upper Airway Stimulation (UAS) is a well-established therapy option for obstructive sleep apnea (OSA). AIMS: There are no data on whether respiratory sensing contributes to successful UAS therapy. MATERIALS & METHODS: After initial measurements of 3 implanted patients (M1), the sensing signal was inverted (M2) without changing other parameters. Two weeks later, the signal was converted back again, and the sensitivity of breathing cycle detection was turned to a very low state (M3). RESULTS: At M2 and M3, the apnea-hypopnea index and oxygen desaturation index increased. DISCUSSION: Correct respiratory sensing is important for controlling OSA using UAS. CONCLUSIONS: Therefore, implant centers should should optimize respiratory sensing placement and adjustment.

Specific podocin mutations correlate with age of onset in steroid-resistant nephrotic syndrome.

Mutations in the gene encoding podocin (NPHS2) cause autosomal recessive steroid-resistant nephrotic syndrome (SRNS). For addressing the possibility of a genotype-phenotype correlation between podocin mutations and age of onset, a worldwide cohort of 430 patients from 404 different families with SRNS were screened by direct sequencing. Recessive podocin mutations were present in 18.1% (73 of 404) of families with SRNS, and 69.9% of these mutations were nonsense, frameshift, or homozygous R138Q. Patients with these mutations manifested symptoms at a significantly earlier age (mean onset <1.75 years) than any other patient group, with or without podocin mutations, in this study (mean onset >4.17 yr). All but one patient affected by truncating or homozygous R138Q mutations developed SRNS before 6 yr of age. Patient groups with other recessive podocin mutations, with single heterozygous podocin mutations, with sequence variants, and with no podocin changes could not be distinguished from each other on the basis of age of onset. In conclusion, nephrotic syndrome in children with truncating or homozygous R138Q mutations manifests predominantly before 6 yr of life, and the onset of disease is significantly earlier than for any other podocin mutations. Because the age of onset can vary by several years among those with identical mutations, additional factors may modify the phenotype.

Upper-Airway Stimulation Before, After, or Without Uvulopalatopharyngoplasty: A Two-Year Perspective.

OBJECTIVE: Upper airway stimulation (UAS) is an effective second-line treatment for obstructive sleep apnea (OSA). In certain patients, there is a considerable need for advanced programming, notably with inadequate palatal response to therapy. The aim of the study was to investigate the impact of uvulopalatopharyngoplasty and tonsillectomy (UPPP-TE) on UAS therapy outcomes from a 2-year perspective after implantation. METHODS: This study included all consecutive patients implanted with UAS in which a full set of 1- and 2-year follow-up assessments (M12 and M24) were obtained. Cases were analyzed in three groups: patients with UPPP-TE after (group 1) and before (group 2) UAS, and those without UPPP-TE (group 3). RESULTS: Therapy success could be achieved in about 80% of the entire cohort. Groups 2 and 3 did not differ significantly with regard to obesity, Apnea-Hypopnea Index, or Oxygen Desaturation Index. With regard to initial sleep endoscopy, there were fewer patients without any obstruction at the palatal and oropharyngeal levels and higher prevalence of lateral obstruction patterns at oropharynx in group 1 in contrast to groups 2 and 3. Groups 2 and 3 showed similar results, although group 2 patients underwent UPPP-TE before UAS implantation. CONCLUSION: UPPP-TE should be considered in patients with persistent OSA after UAS implantation if the obstruction is identified at the level of velum and oropharynx. Although this approach has higher response rates and better outcomes can be achieved in patients with UAS, there is no indication for patients to routinely undergo UPPP-TE prior to UAS implantation. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:514-518, 2019.

Outcome after one year of upper airway stimulation for obstructive sleep apnea in a multicenter German post-market study.

OBJECTIVE/HYPOTHESIS: Upper airway stimulation (UAS) of the hypoglossal nerve has been implemented in the routine clinical practice for patients with moderate-to-severe obstructive sleep apnea (OSA) who could not adhere to continuous positive airway pressure. This study reports objective and patient-reported outcome after 12 months of implantation. STUDY DESIGN: Multicenter prospective single-arm study. METHODS: Consecutive patients who received the UAS system (Inspire Medical Systems, Inc., Minneapolis, Minnesota, Maple Grove, MN, U.S.A.) were enrolled in three German centers. Key study exclusion criteria included body mass index > 35 kg/m2 , apnea-hypopnea index (AHI) < 15 or > 65, or complete concentric collapse at the soft palate during sedated endoscopy. Data collection at 6- and 12-month visit include home sleep test and patient-reported outcome measures. RESULTS: Among the total of 60 participants, the median AHI reduced from 28.6 to 9.5 from baseline to 12 months. Patient-reported outcome measured in Epworth Sleepiness Scale and Functional Outcomes of Sleep Questionnaire both improved significantly from baseline to 12 months. The average usage time was 39.1 ± 14.9 hours per week among all participants based on recordings by the implanted device. One patient requested a removal of the device for cosmetic and other personal reasons and was completed without sequelae. CONCLUSION: This study supported that UAS is a safe and effective treatment option for patients with OSA in routine clinical practice. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:509-515, 2018.

Selective upper airway stimulation in older patients.

OBJECTIVE: Selective stimulation of the hypoglossal nerve has proven to be an effective therapy for patients with obstructive sleep apnea (OSA). The aim of the study is to investigate the efficacy of selective upper airway stimulation (sUAS) in older adults. METHODS: All consecutive patients older than 64 years and who received an implant for sUAS were enrolled. As a control group, an equal number of patients younger than 65 years with matched apnea hypopnea index (AHI) and body-mass-index (BMI) were selected. Treatment outcome data were collected including daytime sleepiness as well as demographics with co-morbidities, BMI, adverse events and adherence to therapy. RESULTS: 62 patients were included. Both the control and study group did not differ significantly for AHI, BMI, and Epworth Sleepiness Scale (ESS) (28.7-28.4/h; 30.1 to 28.4 kg/m2; 14.6 to 12.0 points); but co-morbidities were significantly higher in the study group. Our data showed no significant difference between the outcomes of study and control group for AHI, Oxygen desaturation index (ODI) and ESS (6.0-6.0/h; 7.9 to 5.5/h; 5.0 to 7.0 points). Serious adverse events did not occur in both groups and surgical implantation time did not differ. CONCLUSION: sUAS leads to significant reductions of AHI, ODI and ESS in older patients. Despite higher age and more co-morbidities, surgical implantation time was not affected. Older patients showed higher usage of sUAS. Advanced age seems not to be a limiting factor for treatment outcomes of sUAS, thus indication for this treatment can also be applied to older people.

Pathogenetic and Clinical Aspects of Anti-Neutrophil Cytoplasmic Autoantibody-Associated Vasculitides.

Anti-neutrophil cytoplasmic autoantibodies (ANCA) targeting proteinase 3 (PR3) and myeloperoxidase expressed by innate immune cells (neutrophils and monocytes) are salient diagnostic and pathogenic features of small vessel vasculitis, comprising granulomatosis with polyangiitis (GPA), microscopic polyangiitis, and eosinophilic GPA. Genetic studies suggest that ANCA-associated vasculitides (AAV) constitute separate diseases, which share common immunological and pathological features, but are otherwise heterogeneous. The successful therapeutic use of anti-CD20 antibodies emphasizes the prominent role of ANCA and possibly other autoantibodies in the pathogenesis of AAV. However, to elucidate causal effects in AAV, a better understanding of the complex interplay leading to the emergence of B lymphocytes that produce pathogenic ANCA remains a challenge. Different scenarios seem possible; e.g., the break of tolerance induced by a shift from non-pathogenic toward pathogenic autoantigen epitopes in inflamed tissue. This review gives a brief overview on current knowledge about genetic and epigenetic factors, barrier dysfunction and chronic non-resolving inflammation, necro-inflammatory auto-amplification of cellular death and inflammation, altered autoantigen presentation, alternative complement pathway activation, alterations within peripheral and inflamed tissue-residing T- and B-cell populations, ectopic lymphoid tissue neoformation, the characterization of PR3-specific T-cells, properties of ANCA, links between autoimmune disease and infection-triggered pathology, and animal models in AAV.

Multicenter study on the diagnostic value of a new RIA for the detection of free plasma metanephrines in the work-up for pheochromocytoma.

Available laboratory test methods for the detection of elevated concentrations of catecholamines and their metabolites in urine and/or plasma are not always sensitive enough for the detection of pheochromocytoma. High-quality immunoassays for these compounds appear to be as accurate as high-pressure liquid chromatography (HPLC) or gas chromatography/mass spectrometry (GC-MS). Therefore, the current project aims to establish a new sensitive radioimmunoassay (RIA) for the measurement of free metanephrines in the plasma of patients in the work-up for pheochromocytoma. We report first results of an ongoing multicenter clinico-chemical evaluation study in hypertensive patients and normotensive volunteers. After an overnight fast plasma samples were collected on ice in EDTA- and heparin-coated tubes after insertion of an indwelling venous line and resting in the supine (patients) or sitting position (normal volunteers) for 30 min. Plasma metanephrines were measured by a newly developed RIA from IBL, Hamburg, Germany. Good agreement of the assay with the tandem mass spectrometry (LC-MS/MS) method for normetanephrine (r2=0.975) and for metanephrine (r2=0.985) could be demonstrated. Both specimens, EDTA and heparin plasma, can be used with the same results. The RIA has a good precision of <15% in the normal range and of <10% in the elevated concentration range. Our preliminary data suggest a high validity of the newly developed RIA for measuring free metanephrine and normetanephrine in hypertensive subjects in both EDTA and heparin plasma. Further work is required to determine the accuracy of the test in larger patient populations and in patients with pheochromocytoma.

Botulinum toxin for salivary disorders in the treatment of head and neck cancer.

BACKGROUND/AIM: During the treatment of head and neck cancer (HNC), salivary problems may impair a patient's healing process. Botulinum toxin (BoNT) is accepted as an effective treatment option for reducing salivary flow. We aimed to describe the features of patients treated with BoNT to determine the effects of BoNT. PATIENTS AND METHODS: Twenty-five patients over a five-year period were retrospectively included. The patients suffered at different stages of oncologic treatment. The cohort primarily had larger primary tumors that required complex oncological treatment. RESULTS: The condition improved in more than three quarters of the 19 patients with functional hypersalivation. Four of six cases suffering from a salivary fistula demonstrated an obvious reduction in symptoms. CONCLUSIONS: Injection of BoNT, to temporarily reduce saliva flow, is a safe tool in the treatment of HNC even in situations involving repeated therapy or high dosage. The main clinical side-effect of BoNT is insufficient reduction of the salivary problem.