Oncological and functional outcome after laryngectomy for laryngeal and hypopharyngeal cancer: a population-based analysis in Germany from 2001 to 2020.

Prognostic factors for overall survival (OS), percutaneous endoscopic gastrostomy (PEG) dependency, and long-term speech rehabilitation via voice prosthesis (VP) after laryngectomy for laryngeal or hypopharyngeal cancer were investigated in a retrospective population-based study in Thuringia, Germany. A total of 617 patients (68.7% larynx; hypopharynx; 31.3%; 93.7% men; median age 62 years; 66.0% stage IV) from 2001 to 2020 were included. Kaplan-Meier and Cox multivariable regression analyses were performed. 23.7% of patients received a PEG. 74.7% received a VP. Median OS was 131 months. Independent factors for lower OS were stage IV (compared to stage II; hazard ratio [HR] = 3.455; confidence interval [CI] 1.395-8.556) and laryngectomy for a recurrent disease (HR = 1.550; CI 1.078-2.228). Median time to PEG removal was 7 months. Prior partial surgery before laryngectomy showed a tendency for independent association for later PEG removal (HR = 1.959; CI 0.921-4.167). Postoperative aspiration needing treatment was an independent risk factor (HR = 2.679; CI 1.001-7.167) for later definitive VP removal. Laryngectomy continuously plays an important role in a curative daily routine treatment setting of advanced laryngeal or hypopharyngeal cancer in Germany. Long-term dependency on nutrition via PEG is an important issue, whereas use of VP is a stable long-term measure for voice rehabilitation.

Effect of the German tonsillitis guideline on indication for tonsil surgery in patients with recurrent acute tonsillitis: a population-based study.

Evidence-based indication for tonsil surgery in patients with recurrent acute tonsillitis (RAT) is an ongoing matter of debate. Since introduction of the German tonsillitis guideline in 2015, the indication criteria for tonsil surgery have become much stricter. It is unclear, if this has changed the indication policy. A retrospective population-based study was performed including all 1398 patients with RAT admitted for tonsil surgery in all Thuringian hospitals in 2011, 2015, and 2019. Changes over the years concerning patients' characteristics, number of tonsillitis episodes in the last 12 months treated with antibiotics (T12), and decision for tonsillectomy or tonsillotomy were analyzed using univariable and multivariable statistics. The surgical rates decreased from 28.56/100,000 population in 2011 to 23.57 in 2015, and to 11.60 in 2019. The relative amount of patients with ≥ 6 T12 increased from 14.1% in 2011 over 13.3% in 2015 to 35.9% in 2019. Most patients received a tonsillectomy (98% of all surgeries). Decision for tonsillotomy was seldom (1.2%). Multinomial logistic regression analysis with the year 2011 as reference showed that compared to the year 2015, the age of the patients undergoing surgery increased in 2015 (Odds ratio [OR] = 1.024; 95% confidence interval [CI] = 1.014-1.034; p < 0.001), and also in 2019 (OR 1.030: CI 1.017-1.043; p < 0.001). Compared to 2011, the number T12 was not higher in 2015, but in 2019 (OR 1.273; CI 1.185-1.367; p < 0.001). Stricter rules led to lower tonsil surgery rates but to a higher proportion of patients with ≥ 6 T12 before surgery. Tonsillectomy remained the dominating technique.

Patients with non-idiopathic sudden sensorineural hearing loss show hearing improvement more often than patients with idiopathic sudden sensorineural hearing loss.

INTRODUCTION: To compare inpatient treated patients with idiopathic (ISSNHL) and non-idiopathic sudden sensorineural hearing loss (NISSNHL) regarding frequency, hearing loss, treatment and outcome. METHODS: All 574 inpatient patients (51% male, median age: 60 years) with ISSNHL and NISSNHL, who were treated in federal state Thuringia in 2011 and 2012, were included retrospectively. Univariate and multivariate statistical analyses were performed. RESULTS: ISSNHL was diagnosed in 490 patients (85%), NISSNHL in 84 patients (15%). 49% of these cases had hearing loss due to acute otitis media, 37% through varicella-zoster infection or Lyme disease, 10% through Menière disease and 7% due to other reasons. Patients with ISSNHL and NISSNHL showed no difference between age, gender, side of hearing loss, presence of tinnitus or vertigo and their comorbidities. 45% of patients with ISSNHL and 62% with NISSNHL had an outpatient treatment prior to inpatient treatment (p < 0.001). The mean interval between onset of hearing loss to inpatient treatment was shorter in ISSNHL (7.7 days) than in NISSNHL (8.9 days; p = 0.02). The initial hearing loss of the three most affected frequencies in pure-tone average (3PTAmax) scaled 72.9 dBHL ± 31.3 dBHL in ISSNHL and 67.4 dBHL ± 30.5 dBHL in NISSNHL. In the case of acute otitis media, 3PTAmax (59.7 dBHL ± 24.6 dBHL) was lower than in the case of varicella-zoster infection or Lyme disease (80.11 dBHL ± 34.19 dBHL; p = 0.015). Mean absolute hearing gain (Δ3PTAmaxabs) was 8.1 dB ± 18.8 dB in patients with ISSNHL, and not different in NISSNHL patients with 10.2 dB ± 17.6 dB. A Δ3PTAmaxabs ≥ 10 dB was reached in 34.3% of the patients with ISSNHL and to a significantly higher rate of 48.8% in NISSNHL patients (p = 0.011). CONCLUSIONS: ISSNHL and NISSNHL show no relevant baseline differences. ISSNHL tends to have a higher initial hearing loss. NISSHNL shows a better outcome than ISSNHL.

30-day readmission rate in pediatric otorhinolaryngology inpatients: a retrospective population-based cohort study.

OBJECTIVES: Analysis of frequency and reasons for planned and unplanned 30-day readmission in hospitalized pediatric otorhinolaryngology patients using German Diagnosis Related Group (G-DRG) system data. METHODS: A retrospective population-based cohort study in Thuringia, Germany, was performed for the year 2015 with 2440 cases under 18 years (55.6% male) out of a total number of 15.271 inpatient cases. The majority of pediatric patients were from 2 to 5 years old (54.5%). The most frequent diagnoses were hyperplasia of adenoids or/and tonsils (26.6%). 36 cases (1.5%) experienced readmission within 30-days. RESULTS: 30-day readmission was planned in 9 cases (25% of all readmission) and was unplanned in 27 cases (75%). The median interval between index and readmission treatment was 8 days. Postoperative bleeding after adenoidectomy, tonsillotomy/tonsillectomy or tracheostomy (33.4%) and infectious complications after surgery like acute otitis media, abscess formation or fever (36.2%) were the most frequent reasons for 30-day readmission. Compared to adults treated in 2015 in Thuringia, the readmission rate was higher in adult patients (8.9%) than in this pediatric cohort. In contrast to children, readmissions in adults were mainly planned (65.1%) with a different spectrum of underlying diseases and reasons for readmission. CONCLUSION: The 30-day readmission rate seemed to be lower for pediatric otolaryngology patients compared to adult patients. Unplanned readmissions dominated in pediatric patients, whereas planned readmissions dominated in adults.

Hippocampal hyperactivity in a rat model of Alzheimer's disease.

Neuronal network dysfunction is a hallmark of Alzheimer's disease (AD). However, the underlying pathomechanisms remain unknown. We analyzed the hippocampal micronetwork in transgenic McGill-R-Thy1-APP rats (APPtg) at the beginning of extracellular amyloid beta (Aß) deposition. We established two-photon Ca2+ -imaging in vivo in the hippocampus of rats and found hyperactivity of CA1 neurons. Patch-clamp recordings in brain slices in vitro revealed increased neuronal input resistance and prolonged action potential width in CA1 pyramidal neurons. We did neither observe changes in synaptic inhibition, nor in excitation. Our data support the view that increased intrinsic excitability of CA1 neurons may precede inhibitory dysfunction at an early stage of Aß-deposition and disease progression.

Spray congealed solid lipid microparticles as a sustained release delivery system for Gonadorelin [6-D-Phe]: Production, optimization and in vitro release behavior.

Sustained release lipid microparticles for a potential veterinary application were produced by the means of spray congealing using saturated triglycerides with respective surfactants. The spray congealing process was optimized using unloaded and loaded microparticles, revealing the highest impact of the spray flow on material loss. Yield could be optimized by increasing the spray flow as well as a reduction of the melt temperature from 90 to 75 °C. For the delivery system developed in this study, a release of around 15 days was targeted. The release profile was in first hand determined with the use of model substances (aspartame and tryptophan), before incorporating the decapeptide Gonadorelin [6-D-Phe]. Release could be controlled between 2 and 28 d, which was dependent on stability of microparticles upon incubation, type and concentration of emulsifier, as well as the used triglyceride. Differential scanning calorimetry and X-ray powder diffraction confirmed the crystallization behavior of C14 and C16-triglycerides in combination with various emulsifiers in different modification without impact on release.

A MicroRNA Network Controls Legionella pneumophila Replication in Human Macrophages via LGALS8 and MX1.

Legionella pneumophila is an important cause of pneumonia. It invades alveolar macrophages and manipulates the immune response by interfering with signaling pathways and gene transcription to support its own replication. MicroRNAs (miRNAs) are critical posttranscriptional regulators of gene expression and are involved in defense against bacterial infections. Several pathogens have been shown to exploit the host miRNA machinery to their advantage. We therefore hypothesize that macrophage miRNAs exert positive or negative control over Legionella intracellular replication. We found significant regulation of 85 miRNAs in human macrophages upon L. pneumophila infection. Chromatin immunoprecipitation and sequencing revealed concordant changes of histone acetylation at the putative promoters. Interestingly, a trio of miRNAs (miR-125b, miR-221, and miR-579) was found to significantly affect intracellular L. pneumophila replication in a cooperative manner. Using proteome-analysis, we pinpointed this effect to a concerted downregulation of galectin-8 (LGALS8), DExD/H-box helicase 58 (DDX58), tumor protein P53 (TP53), and then MX dynamin-like GTPase 1 (MX1) by the three miRNAs. In summary, our results demonstrate a new miRNA-controlled immune network restricting Legionella replication in human macrophages.IMPORTANCE Cases of Legionella pneumophila pneumonia occur worldwide, with potentially fatal outcome. When causing human disease, Legionella injects a plethora of virulence factors to reprogram macrophages to circumvent immune defense and create a replication niche. By analyzing Legionella-induced changes in miRNA expression and genomewide chromatin modifications in primary human macrophages, we identified a cell-autonomous immune network restricting Legionella growth. This network comprises three miRNAs governing expression of the cytosolic RNA receptor DDX58/RIG-I, the tumor suppressor TP53, the antibacterial effector LGALS8, and MX1, which has been described as an antiviral factor. Our findings for the first time link TP53, LGALS8, DDX58, and MX1 in one miRNA-regulated network and integrate them into a functional node in the defense against L. pneumophila.

Hospitalization for epistaxis: a population-based healthcare research study in Thuringia, Germany.

PURPOSE: Epistaxis is the most common ENT emergency. The aim was to determine population-based data on severe epistaxis needing inpatient treatment. METHODS: Retrospective population-based cohort study in the federal state Thuringia in 2016 performed on all 840 inpatients treated for epistaxis in otolaryngology departments (60.1% male, median age: 73 years; 63.9% under anticoagulation). The association between patients' and treatment characteristics and longer inpatient stay (≥ 4 days) as well as readmission for recurrent epistaxis was analyzed using univariable and multivariable statistics. RESULTS: The overall incidence of epistaxis needing inpatient treatment was higher for men (42 per 100,000) than for women (28 per 100,000). The highest incidence was reached for men > 85 years (222 per 100,000). Most important independent predictors for longer inpatient stay were localization of the bleeding not in the anterior nose (OR = 2.045; CI = 1.534-2.726), recurrent bleeding during inpatient treatment (OR = 2.142; CI = 1.508-3.042), no electrocoagulation (OR = 2.810; CI = 2.047-3.858), and blood transfusion (OR = 2.731; CI = 1.324-5.635). Independent predictors for later readmission because of recurrent epistaxis were male gender (OR = 1.756; CI = 1.155-2.668), oral anticoagulant use (OR = 1.731; CI = 1.046-2.865), and hereditary hemorrhagic telangiectasia (OR = 13.216; CI 5.102-34.231). CONCLUSIONS: Inpatient treatment of epistaxis seems to be variable in daily routine needing standardization by clinical guidelines and strategies to shorten inpatient treatment and to reduce the risk of readmission.

30-day unplanned readmission rate in otolaryngology patients: A population-based study in Thuringia, Germany.

PURPOSE: Analyze associations between patients' characteristics and treatment factors with 30-day unplanned readmissions in hospitalized otolaryngology patients in the German Diagnosis Related Group (D-DRG) system. METHODS: A retrospective cohort study was performed on 15.271 otolaryngology admissions of 12.859 patients in 2015 in Thuringia, Germany. The medical records of the 1173 cases (7.6%) with readmission within 30-days were analyzed in detail. RESULTS: The 30-day readmission was planned in 747 cases (4.9%) and was unplanned in 422 cases (2.8%). The median interval between primary and next inpatient treatment was 11 days. The principal diagnosis was the same as during the primary index treatment in 72% of the cases. The most frequent reasons for readmission were: Need for non-surgical therapy (31.2%), need for further surgery (26.3%), post-surgical complaints (16.9%), and recurrence of primary complaints (10.7%). The multivariate analysis revealed that discharge due to patient's request against medical advice was a strong independent factor with high risk for unplanned readmission (Odds Ratio [OR] = 9.62]; confidence interval [CI] = 2.69-34.48). Surgery at index admission (OR = 3.33; CI = 1.86-5.96) was the second important independent risk factor for unplanned readmission. Unplanned readmission had more frequently a non-surgical treatment at readmission than a surgical treatment (OR = 3.92; CI = 2.24-6.84) and needed more frequently further diagnostics (OR = 2.34; CI = 1.34-4.11). The following index International Classification of Diseases (ICD) categories had the highest risk for unplanned readmission: Injury, poisoning and certain other consequences of external causes, ICD: S00-T98 (OR = 66.67; CI = 15.87-333.33), symptoms, signs, abnormal findings, ill-defined causes, not otherwise classified, ICD: R00-R99 (OR = 62.5; CI = 11.76-333.33), blood forming organ diseases, ICD: D50-D90 (OR = 21.276; CI = 3.508-125), and eye/ ear diseases, ICD: H00-H95 (OR = 12.66; CI = 4.29-37.03). CONCLUSIONS: The causes of unplanned 30-day readmission in German otolaryngology inpatients are multifactorial. Specific patient and treatment characteristics were identified to be targeted with health care interventions to decrease unplanned readmissions.

Antibacterial activity of a Tribolium castaneum defensin in an in vitro infection model of Streptococcus pneumoniae.

Streptococcus pneumoniae (S. pneumoniae) is the most common bacterial cause of community-acquired pneumonia. Increasing rates of antibiotic-resistant S. pneumoniae strains impair therapy and necessitate alternative treatment options. In this study, we analysed insect-derived antimicrobial peptides (AMPs) for antibacterial effects on S. pneumoniae in a human in vitro infection model.AMP effects on bacterial growth were examined by colony forming unit (CFU)-assays, and growth curve measurements. Furthermore, cytotoxicity to primary human macrophages was detected by measuring lactate-dehydrogenase release to the supernatant. One AMP (Defensin 1) was tested in a model of primary human monocyte-derived macrophages infected with S. pneumoniae strain D39 and a multi-resistant clinical isolate. Inflammatory reactions were characterised by qPCR and multiplex-ELISA.In total, the antibacterial effects of 23 AMPs were characterized. Only Tribolium castaneum Defensin 1 showed significant antibacterial effects against S. pneumoniae strain D39 and a multi-resistant clinical isolate. During in vitro infection of primary human macrophages with S. pneumoniae D39, Defensin 1 displayed strong antibacterial effects, and consequently reduced bacteria-induced cytokine expression and release.In summary, Tribolium castaneum Defensin 1 showed profound antibacterial effectivity against Streptococcus pneumoniae D39 and a multi-resistant clinical isolate without unwanted cytotoxic or inflammatory side effects on human blood-derived macrophages.

[The Swollen Leg in Vascular Medical Practice]. / Das geschwollene Bein in der gefäßmedizinischen Praxis.

In case of an acute leg swelling a deep leg vein thrombosis needs to be excluded. In order to do this, compression sonography and the D-dimer-test are applied in the framework of an established diagnostic algorithm. The ensuing therapy consists in anticoagulation and compression.In case of a chronic leg swelling anamnesis and a clinical check-up often lead to a differential diagnosis. Chronic venous insufficiency is a generic term for a disturbed venous backflow. It is caused by an obstruction or an antegrade or retrograde flow insufficiency. Most common diseases in this context are varicosis or a post-thrombotic syndrome. Sonography and special function tests provide a diagnosis. The basic therapy consists in regular exercise, normalization of weight and compression therapy. In case of a hemodynamically relevant varicose vein surgery or endovascular treatment is advisable. The post-thrombotic syndrome must be treated consistently with the basic therapy.A lymphedema may be hereditary or acquired. In a first step diseases like neoplasia need to be excluded. The initial therapy consists in manual lymph drainage in combination with special compression bandages. Flat knit stockings should be prescribed. Surgical treatment is reserved for special circumstances.A lipedema is clinically diagnosed. It is characterized by lipohypertrophia, pressure sensitivity of the tissue and susceptibility to hematomas. Treatment options include weight reduction, regular exercise, lymph drainage and compression therapy, in some cases liposuction.

Inpatient treatment of patients with idiopathic sudden sensorineural hearing loss: a population-based healthcare research study.

PURPOSE: The aim was to determine inpatient treatment rates of idiopathic sudden sensorineural hearing loss (ISSNHL) with focus on diagnostics, treatment, and outcome. METHODS: A retrospective population-based study in the federal state Thuringia in 2011 and 2012 was performed on all 490 inpatients (51% females, median age: 60 years) treated for ISSNHL (Median duration: 7 days). The association between analyzed parameters and the probability of recovery was tested using univariable and multivariable statistics. RESULTS: The inpatient treatment rate for ISSNHL was 11.23 per 100,000. 172 patients (35%) had an outpatient treatment prior to inpatient treatment. For pure-tone audiometry of the three most affected frequencies (3PTAmax), the initial median hearing loss was 66.67 dB, the median absolute hearing gain ΔPTAabs was 10.0 dB, and the median relative hearing gain in relation with the contralateral side ΔPTArel contral was 30.86%. 51% of the patients reached a ΔPTAabs of ≥ 10 dB. About 2 of 5 patients recovered to a ΔPTArel contral ≥ 50% or reached ≤ 10 dB of contralateral ear. The multivariate analysis revealed that an ISSNHL on the left side [Hazard ratio (HR) = 1.6.88; confidence interval (CI) = 1.161-2.454], no down-sloping audiogram type (HR = 2.016; CI = 1.391-2.921), and no prior outpatient prednisolone treatment (HR = 2.374; CI = 1.505-3.745) were independent factors associated with better recovery (ΔPTAabs ≥ 10 dB). CONCLUSION: Inpatient treatment of ISSNHL is variable in daily practice. The population-based recovery rate was worse than reported in clinical trials. More standardization and clearer criteria for outpatient, inpatient, and salvage therapy are needed.

[Direct Microlaryngoscopy: A Population-Based Analysis on Outcome, Complications and Surgery Rates]. / Mikrolaryngoskopie: Eine populationsbezogene Analyse zu Outcome, Komplikationen und Operationsraten.

Although microlaryngoscopy is an integral part of surgical routine of otorhinolaryngologists, there is no population-based data published on surgery rates and efficiency of microlaryngoscopy country-wide or nation-wide. All 616 patients who underwent microlaryngoscopy 2011 in one of the eight ENT departments in Thuringia were analyzed according to patients' characteristics, therapy, complications and follow-up. The majority of admissions were performed because of a benign disease (60%) of the larynx, and in 33% related to a malignant disease or suspicion of a malignant disease. When a benign disease was suspected, it was confirmed 98% of cases. When a malignant tumor was suspected, it was confirmed in 51% of cases, i. e. ruled out in 49% of cases. Transient laryngeal edema (22%) and bleeding needing revision surgery (1%) were the most frequent or serve observed postoperative sequelae. Teeth damage occurred only in 2 cases (0.2%). A recurrence of the primary disease was observed in 14%. Longer surgery time was an independent predictor for postoperative bleeding and for postoperative laryngeal edema (p=0.050 and p=0.013, respectively). Revision surgery (p<0.0001) and a final diagnosis of a malignant disease (p=0.017) were independent predictors for recurrence of the primary disease. The overall incidence of microlaryngoscopy was 22.98/100000 population. The highest incidence was seen for patients 50-59 years of age with 39.76/100000. Benign diseases were the most frequent indication with 19.33/100000. This population-based analysis is showing that microlaryngoscopy is performed effectively and with low postoperative risks in daily routine of otorhinolaryngologists.

Legionella pneumophila Outer Membrane Vesicles: Isolation and Analysis of Their Pro-inflammatory Potential on Macrophages.

Bacteria are able to secrete a variety of molecules via various secretory systems. Besides the secretion of molecules into the extracellular space or directly into another cell, Gram-negative bacteria can also form outer membrane vesicles (OMVs). These membrane vesicles can deliver their cargo over long distances, and the cargo is protected from degradation by proteases and nucleases. Legionella pneumophila (L. pneumophila) is an intracellular, Gram-negative pathogen that causes a severe form of pneumonia. In humans, it infects alveolar macrophages, where it blocks lysosomal degradation and forms a specialized replication vacuole. Moreover, L. pneumophila produces OMVs under various growth conditions. To understand the role of OMVs in the infection process of human macrophages, we set up a protocol to purify bacterial membrane vesicles from liquid culture. The method is based on differential ultracentrifugation. The enriched OMVs were subsequently analyzed with regard to their protein and lipopolysaccharide (LPS) amount and were then used for the treatment of a human monocytic cell line or murine bone marrow-derived macrophages. The pro-inflammatory responses of those cells were analyzed by enzyme-linked immunosorbent assay. Furthermore, alterations in a subsequent infection were analyzed. To this end, the bacterial replication of L. pneumophila in macrophages was studied by colony-forming unit assays. Here, we describe a detailed protocol for the purification of L. pneumophila OMVs from liquid culture by ultracentrifugation and for the downstream analysis of their pro-inflammatory potential on macrophages.

The immunosuppressive domain of the transmembrane envelope protein gp41 of HIV-1 binds to human monocytes and B cells.

The induction of the acquired immunodeficiency syndrome by the human immunodeficiency virus-1 (HIV-1) is a complex process which is not yet understood in full detail. Still open is the question whether the highly conserved so-called immunosuppressive (Isu) domain in the transmembrane envelope (TM) protein gp41 of HIV-1 is actively participating in immunopathogenesis. Inactivated virus particles, recombinant gp41 and peptides corresponding to the Isu domain have been reported to inhibit lymphocyte proliferation, as well as to alter cytokine release and gene expression. Here we demonstrate, using fluorescence-activated cell sorting and competition experiments, that homopolymers of the Isu peptide of HIV-1 are binding specifically to human peripheral blood mononuclear cells, mainly to monocytes and B cells. These data suggest that a putative receptor might be involved in the immunomodulatory effects observed previously.

Pediatric adenoidectomy: a population-based regional study on epidemiology and outcome.

OBJECTIVES: To evaluate population-based data on incidence of pediatric adenoidectomy and rate of revision surgery. METHODS: A retrospective study of all adenoidectomies in children was performed in the year 2009 in all otolaryngology departments in one federal state, Thuringia, in Germany. Patients' characteristics, preoperative diagnostics and postoperative complications were analyzed. The association between baseline characteristics and the risk of re-adenoidectomy was examined using Kaplan-Meier method with univariate log-rank test, and with a multivariate Cox regression model. Population data were used to calculate age-related annual rates of adenoidectomies. RESULTS: 1939 adenoidectomies were performed in 2009 in Thuringia. 89% were primary cases and 11% of the children already had an adenoidectomy prior to 2009. Immediate re-surgery because of primary hemorrhage was necessary in 0.8% of the cases. Re-adenoidectomy because of recurrent symptoms was needed in 9% of patients after a median interval of 16 months. The univariate analysis showed that the factors age ≤3 years and primary surgery were significantly associated to a higher risk of surgery because of recurrent symptoms The multivariate analysis showed that primary surgery was independently associated with the risk of re-surgery (hazard ratio 1.66; 95% confidence interval 1.01-2.74). The annual adenoidectomy rate was 678/100,000 underage habitants. The incidence was highest between 2 and 4 years of age. CONCLUSIONS: This population based analysis is showing that adenoidectomy is performed country-wide with good results and low risk on important scale in daily routine by otorhinolaryngologists. The risk of re-adenoidectomy seems to be higher than hitherto reported by hospital-based studies.

Middle ear surgery in Thuringia, Germany: a population-based regional study on epidemiology and outcome.

OBJECTIVE: To evaluate population-based data on incidence and efficiency of middle ear surgery. STUDY DESIGN: Retrospective review. SETTING: All otolaryngology departments in one federal state in Germany. PATIENTS: All 1,037 middle ear surgeries performed in Thuringia in 2005. INTERVENTIONS: Middle ear surgery. MAIN OUTCOME MEASURE: Analysis of preoperative and postoperative audiometric results, preoperative diagnostics, and postoperative complications. Univariate statistical tests were used to analyze predictors for air-bone gap (ABG) improvement, complications, and need for resurgery. Population data were used to calculate incidences of middle ear diseases admitted for surgery and annual rates of middle ear surgeries. RESULTS: ABG improved after surgery for chronic otitis media without and with cholesteatoma, otosclerosis, trauma cases, or complication after acute otitis media/externa (p < 0.0001; p < 0.0001; p < 0.0001; p = 0.005; p = 0.004; respectively). Middle ear surgery significantly improved bone conduction in cases of otosclerosis (p = 0.008), sudden deafness (p = 0.006), and acute otitis media/externa with complication (p = 0.004). There was a trend of more complication in patients older than 60 years (p = 0.055). Surgery was indicated for chronic otitis media without cholesteatoma in 17.4/100,000 persons, for cholesteatoma in 15.0/100,000, for otosclerosis in 5.7/100,000, for sudden deafness with suspicion of perilymph fistula in 1.5/100,000, and for trauma with affection of the lateral cranial base and hearing loss or otitis media with complication in 1.3/100,000 habitants, respectively. A cochlear implant was indicated in 1.0/100,000 habitants. CONCLUSION: This population based analysis is showing that middle ear surgery is performed country-wide with good results and low risk on important scale in daily routine by ear surgeons.

Polymorphisms of the apoptosis-associated gene DP1L1 (deleted in polyposis 1-like 1) in colon cancer and inflammatory bowel disease.

PURPOSE: The deleted-in-polyposis1-like1 (DP1L1) gene displays pro-apoptotic activity and was proposed to be a tumor suppressor. It locates on chromosome 19p13.3, which harbors the locus for Peutz-Jeghers-Syndrome and is deleted in various tumors. We analyzed the association of DP1L1 polymorphisms with colon cancer, and cancer-associated Ulcerative colitis and Crohn's disease. EXPERIMENTAL DESIGN: Fifty-eight patients with colon cancer, 18 with Ulcerative colitis, 18 with Crohn's disease, and 70 control individuals were genotyped for SNPs at positions 992 and 996 of DP1L1 cDNA. RESULTS: Homozygous carriers of 992A alleles comprised 16% of the control group but were significantly increased in colon cancer with a frequency of 36% (P = 0.013 cancer vs control). Homozygous 991-A was also elevated in Ulcerative colitis (N = 18) with a frequency of 33%. In contrast, 18 patients with Crohn's disease showed no difference in frequency of 992AA (22%) compared to control. The A-allele of the adjacent C996A polymorphism has a low frequency (3.5%) in the control population, but significantly increased frequency of 13% in colon cancer (P = 0.0149 for allele frequency, Fisher's exact). 996-A allele frequency is also increased in inflammatory bowel disease (IBD): 22% of Ulcerative colitis- and 50% of Crohn's disease-patients were heterozygous carriers of 996-A (P = 0.052 for CU and P < 0.0001 for MC vs controls). CONCLUSIONS: DP1L1 polymorphisms are associated with colon cancer and IBD. This indicates that DP1L1 plays a functional role in these conditions. Thus DP1L1 may be a diagnostic and therapeutic target for colon cancer and IBD.

Kinome-wide RNAi screen implicates at least 5 host hepatocyte kinases in Plasmodium sporozoite infection.

Plasmodium sporozoites, the causative agent of malaria, are injected into their vertebrate host through the bite of an infected Anopheles mosquito, homing to the liver where they invade hepatocytes to proliferate and develop into merozoites that, upon reaching the bloodstream, give rise to the clinical phase of infection. To investigate how host cell signal transduction pathways affect hepatocyte infection, we used RNAi to systematically test the entire kinome and associated genes in human Huh7 hepatoma cells for their potential roles during infection by P. berghei sporozoites. The three-phase screen covered 727 genes, which were tested with a total of 2,307 individual siRNAs using an automated microscopy assay to quantify infection rates and qRT-PCR to assess silencing levels. Five protein kinases thereby emerged as top hits, all of which caused significant reductions in infection when silenced by RNAi. Follow-up validation experiments on one of these hits, PKCsigma (PKCzeta), confirmed the physiological relevance of our findings by reproducing the inhibitory effect on P. berghei infection in adult mice treated systemically with liposome-formulated PKCsigma-targeting siRNAs. Additional cell-based analyses using a pseudo-substrate inhibitor of PKCsigma added further RNAi-independent support, indicating a role for host PKCsigma on the invasion of hepatocytes by sporozoites. This study represents the first comprehensive, functional genomics-driven identification of novel host factors involved in Plasmodium sporozoite infection.

Synthesis, biological evaluation, and molecular modeling studies of methylene imidazole substituted biaryls as inhibitors of human 17alpha-hydroxylase-17,20-lyase (CYP17)--part II: Core rigidification and influence of substituents at the methylene bridge.

Thirty-five novel substituted imidazolyl methylene biphenyls have been synthesized as CYP17 inhibitors for the potential treatment of prostate cancer. Their activities have been tested with recombinant human CYP17 expressed in Escherichia coli. Promising compounds were tested for selectivity against CYP11B1, CYP11B2, and hepatic CYP enzymes 3A4, 1A2, 2B6 and 2D6. The core rigidified compounds (30-35) were the most active ones, being much more potent than Ketoconazole and reaching the activity of Abiraterone. However, they were not very selective. Another rather potent and more selective inhibitor (compound 23, IC(50)=345 nM) was further examined in rats regarding plasma testosterone levels and pharmacokinetic properties. Compared to the reference Abiraterone, 23 was more active in vivo, showed a longer plasma half-life (10h) and a higher bioavailability. Using our CYP17 homology protein model, docking studies with selected compounds were performed to study possible interactions between inhibitors and amino acid residues of the active site.