High-Dose Glucocorticoids for the Treatment of Sudden Hearing Loss.

BACKGROUND: Systemic glucocorticoids are commonly used for primary therapy of idiopathic sudden sensorineural hearing loss (ISSNHL). However, the comparative effectiveness and risk profiles of high-dose over lower-dose regimens remain unknown. METHODS: We randomly assigned patients with sudden hearing loss of greater than or equal to 50 dB within 7 days from onset to receive either 5 days of high-dose intravenous prednisolone at 250 mg/d (HD-Pred), 5 days of high-dose oral dexamethasone at 40 mg/d (HD-Dex), or, as a control, 5 days of oral prednisolone (Pred-Control) at 60 mg/d followed by 5 days of tapering doses. The primary outcome was the change in hearing threshold (pure tone average) in the three most affected contiguous frequencies from baseline to day 30. Secondary outcomes included speech understanding, tinnitus, communication competence, quality of life, hypertension, and insulin resistance. RESULTS: A total of 325 patients were randomly assigned. Mean change in 3PTAmost affected hearing threshold from baseline to 30 days was 34.2 dB (95% CI, 28.4 to 40.0) in the HD-Pred group, 41.4 dB (95% CI, 35.6 to 47.2) in the HD-Dex group, and 41.0 dB (95% CI, 35.2 to 46.8) in the Pred-Control group (P=0.09 for analysis of variance). There were more adverse events related to trial medication in the HD-Pred (n=73) and HD-Dex (n=76) groups than in the Pred-Control group (n=46). CONCLUSIONS: Systemic high-dose glucocorticoid therapy was not superior to a lower-dose regimen in patients with ISSNHL, and it was associated with a higher risk of side effects. (Funded by the Federal Ministry of Education and Research [BMBF]; EudraCT number, 2015­002602­36.)

Osteosynthesis of Phalangeal Fractures: Biomechanical Comparison of Kirschner Wires, Plates, and Compression Screws.

PURPOSE: The aim of this study was to compare several osteosynthesis techniques (intramedullary headless compression screws, T-plates, and Kirschner wires) for distal epiphyseal fractures of proximal phalanges in a human cadaveric model. METHODS: A total of 90 proximal phalanges from 30 specimens (index, ring, and middle fingers) were used for this study. After stripping off all soft tissue, a transverse distal epiphyseal fracture was simulated at the proximal phalanx. The 30 specimens were randomly assigned to 1 fixation technique (30 per technique), either a 3.0-mm intramedullary headless compression screw, locking plate fixation with a 2.0-mm T-plate, or 2 oblique 1.0-mm Kirschner wires. Displacement analysis (bending, distraction, and torsion) was performed using optical tracking of an applied random speckle pattern after osteosynthesis. Biomechanical testing was performed with increasing cyclic loading and with cyclic load to failure using a biaxial torsion-tension testing machine. RESULTS: Cannulated intramedullary compression screws showed significantly less displacement at the fracture site in torsional testing. Furthermore, screws were significantly more stable in bending testing. Kirschner wires were significantly less stable than plating or screw fixation in any cyclic load to failure test setup. CONCLUSIONS: Intramedullary compression screws are a highly stable alternative in the treatment of transverse distal epiphyseal phalangeal fractures. Kirschner wires seem to be inferior regarding displacement properties and primary stability. CLINICAL RELEVANCE: Fracture fixation of phalangeal fractures using plate osteosynthesis may have the advantage of a very rigid reduction, but disadvantages such as stiffness owing to the more invasive surgical approach and soft tissue irritation should be taken into account. Headless compression screws represent a minimally invasive choice for fixation with good biomechanical properties.

A role for nitric oxide in serotonin neurons of the midbrain raphe nuclei.

Neuronal nitric oxide synthase (nNOS) catalyses the production of the neurotransmitter nitric oxide. nNOS is expressed in the dorsal raphe nucleus (DRN), a source of ascending serotonergic projections. In this study, we examined the distribution nNOS and the function of nitric oxide in the DRN and adjacent median raphe nucleus (MRN) of the rat. We hypothesized that nNOS is differentially expressed across the raphe nuclei and that nitric oxide influences the firing activity of a subgroup of 5-HT neurons. Immunohistochemistry revealed that, nNOS is present in around 40% of 5-HT neurons, throughout the DRN and MRN, as well as in some non-5-HT neurons immediately adjacent to the DRN and MRN. The nitric oxide receptor, soluble guanylyl cyclase, was present in all 5-HT neurons examined in the DRN and MRN. In vitro extracellular electrophysiology revealed that application of the nitric oxide donor, diethylamine NONOate (30-300 µM) inhibited 60%-70% of putative 5-HT neurons, excited approximately 10% of putative 5-HT neurons and had no effect on the rest. The inhibitory response to nitric oxide was blocked by [1H-[1,2,4]oxadiazolo-[4, 3-a]quinoxalin-1-one (ODQ, 30 or 100 µM), indicating mediation by soluble guanylyl cyclase. Juxtacellular labelling revealed that nitric oxide inhibits firing in both putative 5-HT neurons which express nNOS and those which do not express nNOS. Our data are consistent with the notion that nitric oxide acts as both a trans-synaptic and autocrine signaller in 5-HT neurons in the DRN and MRN and that its effects are widespread and primarily inhibitory.

Alternative to Vein Grafts for Arterial Repair in Avulsion Amputations of Thumb: Case Series.

The first reimplantation of a complete thumb amputation using microvascular anastomosis in a human was successfully conducted by Komatsu in 1968. Avulsion amputations of the thumb at the level of metacarpophalangeal joints pose a tedious task for direct arterial repair, even with adequate bone shortening. Owing to the short length of princeps pollicis from the deep arch, tight working space in the first web under microscope, and the associated intimal injuries, we advise transposing the radial indices artery in such cases which gives adequate length and noninjured artery for a tension-free repair. Using this method, surgeons can avoid the tedious task of vein grafts for arterial repair, reduce the operating time, and improve successful outcomes in thumb reimplantations.

Intramedullary Percutaneous Fixation of Extra-Articular Proximal and Middle Phalanx Fractures.

Multiple methods have been described for treating unstable proximal and middle phalangeal fractures. Irrespective of using an open or closed technique of fixation, stiffness and extensor lag at the proximal/distal interphalangeal joint almost always occur. This issue can be avoided by allowing the patients to mobilize the fingers out of plaster or splint as early as possible from the day of surgery. We describe a technique of intramedullary percutaneous fixation of extra-articular proximal and middle phalanx fractures allowing immediate mobilization of fingers, concurrent stabilization with progressive healing and thus preventing such complications.

Wnt/ß-Catenin Signaling Activation beyond Robust Nuclear ß-Catenin Accumulation in Nondysplastic Barrett's Esophagus: Regulation via Dickkopf-1.

INTRODUCTION: Wnt/ß-catenin signaling activation has been reported only during the late steps of Barrett's esophagus (BE) neoplastic progression, but not in BE metaplasia, based on the absence of nuclear ß-catenin. However, ß-catenin transcriptional activity has been recorded in absence of robust nuclear accumulation. Thus, we aimed to investigate the Wnt/ß-catenin signaling in nondysplastic BE. METHODS: Esophageal tissues from healthy and BE patients without dysplasia were analyzed for Wnt target gene expression by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry. Esophageal squamous (EPC1-& EPC2-hTERT), BE metaplastic (CP-A), and adenocarcinoma (OE33) cell lines were characterized for Wnt activation by qRT-PCR, Western blot, and luciferase assay. Wnt activity regulation was examined by using recombinant Wnt3a and Dickkopf-1 (Dkk1) as well as Dkk1 short interfering RNA. RESULTS: Wnt target genes (AXIN2, c-MYC, Cyclin D1, Dkk1) and Wnt3a were significantly upregulated in nondysplastic BE compared with squamous mucosa. Elevated levels of dephosphorylated ß-catenin were detected in nondysplastic BE. Nuclear active ß-catenin and TOPflash activity were increased in CP-A and OE33 cells compared with squamous cells. Wnt3a-mediated ß-catenin signaling activation was abolished by Dkk1 in CP-A cells. TOPFlash activity was elevated following Dkk1 silencing in CP-A but not in OE33 cells. Dysplastic and esophageal adenocarcinoma tissues demonstrated further Dkk1 and AXIN2 overexpression. CONCLUSIONS: Despite the absence of robust nuclear accumulation, ß-catenin is transcriptionally active in nondysplastic BE. Dkk1 overexpression regulates ß-catenin signaling in BE metaplastic but not in adenocarcinoma cells, suggesting that early perturbation of Dkk1-mediated signaling suppression may contribute to BE malignant transformation.

Anti inflammatory and anti angiogenic effect of black raspberry extract on human esophageal and intestinal microvascular endothelial cells.

Polyphenolic compounds (anthocyanins, flavonoid glycosides) in berries prevent the initiation, promotion, and progression of carcinogenesis in rat's digestive tract and esophagus, in part, via anti-inflammatory pathways. Angiogenesis has been implicated in the pathogenesis of chronic inflammation and tumorigenesis. In this study, we investigated the anti-inflammatory and anti-angiogenic effects of black raspberry extract (BRE) on two organ specific primary human intestinal microvascular endothelial cells, (HIMEC) and human esophageal microvascular endothelial cells (HEMEC), isolated from surgically resected human intestinal and donor discarded esophagus, respectively. HEMEC and HIMEC were stimulated with TNF-α/IL-1ß with or without BRE. The anti-inflammatory effects of BRE were assessed based upon COX-2, ICAM-1 and VCAM-1 gene and protein expression, PGE2 production, NFκB p65 subunit nuclear translocation as well as endothelial cell-leukocyte adhesion. The anti-angiogenic effects of BRE were assessed on cell migration, proliferation and tube formation following VEGF stimulation as well as on activation of Akt, MAPK and JNK signaling pathways. BRE inhibited TNF-α/IL-1ß-induced NFκB p65 nuclear translocation, PGE2 production, up-regulation of COX-2, ICAM-1 and VCAM-1 gene and protein expression and leukocyte binding in HEMEC but not in HIMEC. BRE attenuated VEGF-induced cell migration, proliferation and tube formation in both HEMEC and HIMEC. The anti-angiogenic effect of BRE is mediated by inhibition of Akt, MAPK and JNK phosphorylations. BRE exerted differential anti-inflammatory effects between HEMEC and HIMEC following TNF-α/IL-1ß activation whereas demonstrated similar anti-angiogenic effects following VEGF stimulation in both cell lines. These findings may provide more insight into the anti-tumorigenic capacities of BRE in human disease and cancer.

Endothelial-mesenchymal transition in normal human esophageal endothelial cells cocultured with esophageal adenocarcinoma cells: role of IL-1ß and TGF-ß2.

Endothelial-mesenchymal transition (EndoMT) has been recognized as a key determinant of tumor microenvironment in cancer progression and metastasis. Endothelial cells undergoing EndoMT lose their endothelial markers, acquire the mesenchymal phenotype, and become more invasive with increased migratory abilities. Early stages of esophageal adenocarcinoma (EAC) are characterized by strong microvasculature whose impact in tumor progression remains undefined. Our aim was to determine the role of EndoMT in EAC by investigating the impact of tumor cells on normal primary human esophageal microvascular endothelial cells (HEMEC). HEMEC were either cocultured with OE33 adenocarcinoma cells or treated with IL-1ß and transforming growth factor-ß2 (TGF-ß2) for indicated periods and analyzed for EndoMT-associated changes by real-time PCR, Western blotting, immunofluorescence staining, and functional assays. Additionally, human EAC tissues were investigated for detection of EndoMT-like cells. Our results demonstrate an increased expression of mesenchymal markers [fibroblast-specific protein 1 (FSP1), collagen1α2, vimentin, α-smooth muscle actin (α-SMA), and Snail], decreased expression of endothelial markers [CD31, von Willebrand factor VIII (vWF), and VE-cadherin], and elevated migration ability in HEMEC following coculture with OE33 cells. The EndoMT-related changes were inhibited by IL-1ß and TGF-ß2 gene silencing in OE33 cells. Recombinant IL-1ß and TGF-ß2 induced EndoMT in HEMEC. Although the level of VEGF expression was elevated in EndoMT cells, the angiogenic property of these cells was diminished. In vivo, by immunostaining EndoMT-like cells were detected at the invasive front of EAC. Our findings underscore a significant role for EndoMT in EAC and provide new insights into the mechanisms and significance of EndoMT in the context of tumor progression.

Dickkopf-1, the Wnt antagonist, is induced by acidic pH and mediates epithelial cellular senescence in human reflux esophagitis.

Squamous esophageal epithelium adapts to acid reflux-mediated injury by proliferation and differentiation via signal transduction pathways. Induction of the Wnt antagonist Dickkopf-1 (Dkk1) is involved in tissue repair during inflammation and cellular injury. In this study, we aimed to identify the biological role of Dkk1 in human reflux esophagitis with respect to cell growth and regulation of Wnt signaling. Esophageal biopsies from reflux-esophagitis patients (n = 15) and healthy individuals (n = 10) were characterized in terms of Dkk1 expression. The role of Dkk1 in response to acid-mediated epithelial injury was analyzed by cellular assays in vitro utilizing squamous esophageal epithelial cell lines (EPC1-hTERT, EPC2-hTERT, and HEEC). Dkk1 was significantly overexpressed in human reflux-esophagitis tissue compared with healthy esophageal mucosa at transcriptional and translational levels. After acute and chronic acid (pH 4) exposure, esophageal squamous epithelial cell lines expressed and secreted high levels of Dkk1 in response to stress-associated DNA injury. High extracellular levels of human recombinant Dkk1 inhibited epithelial cell growth and induced cellular senescence in vitro, as demonstrated by reduced cell proliferation, G0/G1 cell cycle arrest, elevated senescence-associated ß-galactosidase activity, and upregulation of p16. Acid pulsing induced Dkk1-mediated senescence, which was directly linked to the ability of Dkk1 to antagonize the canonical Wnt/ß-catenin signaling. In healthy esophageal mucosa, Dkk1 expression was associated with low expression of transcriptionally active ß-catenin, while in reflux-esophagitis tissue, Dkk1 overexpression correlated with increased senescence-associated ß-galactosidase activity and p16 upregulation. The data indicate that, in human reflux esophagitis, Dkk1 functions as a secreted growth inhibitor by suppressing Wnt/ß-catenin signaling and promoting cellular senescence. These findings suggest a significant role for Dkk1 and cellular senescence in esophageal tissue homeostasis during reflux esophagitis.

[Diagnosis and treatment of rib fracture during spontaneous vaginal delivery].

INTRODUCTION: Progress of labor in multiparous women usually is not accompanied with risk of any kind of birth trauma. CASE OUTLINE: We report a very rare case of rib fracture in a neonate during vaginal delivery in the 39/40 week of gestation. The expulsion started spontaneously without any manipulation from the obstetrician. Live male newborn was delivered 4650 g. in weight, 55 cm long, with head circumference of 39 cm, Apgar score 9. The child was immediately examined by the neonatologist. Crepitations were palpable over the left hemithorax, and auscultatory on the left side inspiratory cracks. Finding was suspicious for rib fracture on the left side posteriorly and brachial plexus palsy, while other findings were normal. X-ray finding was inconclusive, but suspicious for fracture of the 4th, 5th, and 6th left rib posteriorly, without dislocation of bone fragments. There were no signs of pneumothorax. Dorsal position of the newborn was considered sufficient, accompanied with analgetics. X-ray was scheduled in a week because formation of the calus would be the only objective sign of previous rib fracture. On the control X-ray fracture lines were clearly visible on the 3rd, 4th, 5th 6th and 7th rib posteriorly, without dislocation of bone fragments with initial calus formation. The child was discharged from hospital in good condition after two weeks, for further outpatient care. CONCLUSION: With timely diagnostics of this very rare intrapartal fracture, adequate treatment, dorsal position and close control of clinical condition of the newborn, serious and potentially life threatening complications can be avoided.

EUK-207 protects human intestinal microvascular endothelial cells (HIMEC) against irradiation-induced apoptosis through the Bcl2 pathway.

AIM: To elucidate the signaling mechanisms involved in the protective effect of EUK-207 against irradiation-induced cellular damage and apoptosis in human intestinal microvasculature endothelial cells (HIMEC). METHODS: HIMECs were irradiated and treated with EUK-207. Using hydroethidine and DCF-DA fluorescent probe the intracellular superoxide and reactive oxygen species (ROS) were determined. By real-time PCR and western blotting caspase-3, Bcl2 and Bax genes and proteins were analyzed. Proliferation was determined by [(3)H]-thymidine uptake. Immunofluorescence staining was used for translocation of p65 NFκB subunit. KEY FINDING: Irradiation increased ROS production, apoptosis, Bax, Caspase3 and NFkB activity in HIMEC and inhibited cell survival/growth/proliferation. EUK-207 restored the endothelial functions, markedly inhibited the ROS, up-regulated the Bcl2 and down-regulated Bax and prevented NFκB caspase 3 activity in HIMEC. SIGNIFICANCE: HIMEC provide a novel model to define the effect of irradiation induced endothelial dysfunction. Our findings suggest that EUK-207 effectively inhibits the damaging effect of irradiation.

Bilateral Monteggia fracture in adults.

INTRODUCTION: In 1814 Giovanni Monteggia first described two cases of fractures of the proximal third of ulna with dislocation of the radial head. These fractures are more common in children than in adults, and mutual Monteggia fracture is a rare complication. This study presents a treatment course of a patient with bilateral Monteggia fracture. CASE REPORT: A 55-year-old patient was injured by falling in the yard. Radiography showed bilateral Monteggia fracture type II (by the Badon classification). Operative treatment of fracture was done by a compression plate on the right side and by the zuggurtung technique on the left one. Closed repositioning of the radial head was done on both sides. The patient was wearing a plaster splint for the upper arm for 21 days. After removing the fixation, the function of the elbow was determined by the Broberg Morrey score (BM) which was on the right side 45.5 and on the left side 47.5. After the proper physical therapy, four months after the surgery, BM score was 100 on the right side, and 93 on the left one. CONCLUSION: Surgical treatment and early rehabilitation is the key for the return of good function of both elbows.

[Length of hospitalization of patients with ankle fracture].

INTRODUCTION: Fractures of ankle are one of the most frequent interacticular fractures that require operative treatment. During the work, the influence of some particular factors (the length of the preoperative period, the complications of the operative period and the application of antibiotics) to the length of the postoperative intrahospital stay, are scrutinised. METHOD: The patients with ankle fracture treated by operation were comprised by the retrospective study in the Traumatologic department in the CHC Zemun in period of 2003 to 2006, and they were divided in three groups depending on the length of postoperative stay. RESULTS: The period of time before the operation (Chi = 0.405, p < 0.01), the appearance of complications (Chi = 0.465, p < 0.01), as well as the length of the period of antibiotic application (Chi = 0.580, p < .01), significantly influence to the length of the postoperative intrahospital stay. The everage length of intrahospital stay for the patients with registered complications was 19 days, while for the patients without registered complications was 10 days. There is statistically significant difference in the length of intrahospital recovery, depending on various complications (logrank = 35.74; df = 5; p < 0.01). CONCLUSION: It is necessary to treat these fractures as soon as possible, for this way of medical treatment results with less number of complications, shorter stay of patients in hospital and thereby reduced treatment costs.

Expression of matrix metalloproteinase-9 (MMP-9) and blood vessel density in laryngeal squamous cell carcinomas.

CONCLUSION: In this study we found that inflammatory cells may be a source of MMP-9 in laryngeal cancer. MMP-9 was correlated with blood vessel density. MMP-9 may be a potential target to disrupt tumor neovascularization. OBJECTIVE: To study the expression of MMP-9 in laryngeal cancer and determine a possible relation with blood vessel density. METHODS: Immunohistochemistry was used for MMP analysis and for blood vessel detection in 83 laryngeal cancer samples. The density of blood vessels was analyzed with a stereological tool. RESULTS: MMP-9 was detected in inflammatory cells. Positivity for MMP-9 correlated significantly with the grade of differentiation (p = 0.025). Expression of MMP-9 was not correlated with T stage, nodal metastasis, or tumor recurrence. The mean blood vessel density was 51.4 vessels/mm². Specimens were more likely to exhibit higher density of blood vessels when MMP-9 expression was also present (p = 0.014).

[Prevention of postpartal endometritis: antibiotic of choice].

INTRODUCTION: In spite of the advances of modern medicine, puerperal infection is still one of the leading causes of morbidity and mortality of women in postpartal period. OBJECTIVE: The aim of this study was to analyse the presence of microorganisms in the cervicovaginal region of women in labour, as well as the frequency of puerperal endometritis in order to determine optimal treatment for isolated microorganisms and to prevent postpartal endometritis. METHODS: In this study, all women who gave birth to a healthy child per vias naturalis during the past two years in a tertiary health institution, Institute of Gynaecology and Obstetrics, Clinical Centre of Serbia, were analysed. The investigation involved 6,391 women in labour. Cervicovaginal smear was taken from all patients before labour, on admission for delivery, and sent to microbiological analysis. Standard procedures of bacterial cultivation were used. For statistical analysis of the results, we used the statistical programme SPSS 15. RESULTS: A single microorganism was isolated from each smear of 612 women and in 52 patients two microorganisms were registered in the same smear. We identified 10 sorts of microorganisms, out of which Escherichia coli (in 43.8% of cases), and Enterococcus spp. (in 27.9% of cases) were the most frequent ones. Due to the appropriate approach, there were no cases of puerperal endometritis registered. Reactivity tests showed that Escherichia coli was sensitive to trimethoprim-sulphamethoxazole, Enterococcus spp. to macrolides and cephalosporines, while both types of microorganisms were sensitive to synthetic penicillins and fluoroquinolines. CONCLUSION: The study results show that 10.9% of pregnant women have positive findings of the cervicovaginal smear and that infection prevention should be directed towards Escherichia coli and Enterococcus spp. by administration of the listed antibiotics.