Ex vivo toxicity of nitrogen dioxide in human nasal epithelium at the WHO defined 1-h limit value.

Current pollution limits indicating potential harm to human health caused by nitrogen dioxide have prompted a variety of studies on the cytotoxicity and genotoxicity of nitrogen dioxide (NO2) in vitro. The present study focuses on toxic effects of NO2 at the WHO defined 1-h limit value of 200 µg NO2/m(3) air, equivalent to 0.1 ppm NO2. Nasal epithelial mucosa cells of 10 patients were cultured as an air-liquid interface and exposed to 0.1 ppm NO2 for 0.5 h, 1 h, 2 h and 3 h and synthetic air as negative control. After exposure, analysis of genotoxicity was performed by the alkaline single cell microgel electrophoresis (comet) assay and by the micronucleus test. Depression of proliferation and cytotoxic effects were checked by the micronucleus assay and the trypan blue exclusion assay. The experiments demonstrated significant DNA fragmentation even at the shortest exposure duration of half an hour in the comet assay. The amount of DNA fragmentation significantly increased with extended NO2 exposure durations. The amount of DNA fragmentation increased with extended exposure durations to synthetic air at a significantly lower level as compared to NO2 exposure. Micronucleus inductions were seen only at the longest exposure duration of 3h. There were no changes in proliferation seen in the micronucleus assay under any experimental setup. Moreover, no signs of necrosis, apoptosis or changes in viability were detected. Data demonstrate genotoxicity of NO2 at concentrations found in the urban atmosphere during short exposure durations. DNA alterations in the micronucleus assay at an exposure time of 3h indicate a significant DNA alteration possibly being hazardous to humans.

Aspects of nitrogen dioxide toxicity in environmental urban concentrations in human nasal epithelium.

Cytotoxicity and genotoxicity of nitrogen dioxide (NO(2)) as part of urban exhaust pollution are widely discussed as potential hazards to human health. This study focuses on toxic effects of NO(2) in realistic environmental concentrations with respect to the current limit values in a human target tissue of volatile xenobiotics, the epithelium of the upper aerodigestive tract. Nasal epithelial cells of 10 patients were cultured as an air-liquid interface and exposed to 0.01 ppm NO(2), 0.1 ppm NO(2), 1 ppm NO(2), 10 ppm NO(2) and synthetic air for half an hour. After exposure, genotoxicity was evaluated by the alkaline single-cell microgel electrophoresis (Comet) assay and by induction of micronuclei in the micronucleus test. Depression of proliferation and cytotoxic effects were determined using the micronucleus assay and trypan blue exclusion assay, respectively. The experiments revealed genotoxic effects by DNA fragmentation starting at 0.01 ppm NO(2) in the Comet assay, but no micronucleus inductions, no changes in proliferation, no signs of necrosis or apoptosis in the micronucleus assay, nor did the trypan blue exclusion assay show any changes in viability. The present data reveal a possible genotoxicity of NO(2) in urban concentrations in a screening test. However, permanent DNA damage as indicated by the induction of micronuclei was not observed. Further research should elucidate the effects of prolonged exposure.

Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience.

Psychiatric neurosurgery teams in the United States and Europe have studied deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule and adjacent ventral striatum (VC/VS) for severe and highly treatment-resistant obsessive-compulsive disorder. Four groups have collaborated most closely, in small-scale studies, over the past 8 years. First to begin was Leuven/Antwerp, followed by Butler Hospital/Brown Medical School, the Cleveland Clinic and most recently the University of Florida. These centers used comparable patient selection criteria and surgical targeting. Targeting, but not selection, evolved during this period. Here, we present combined long-term results of those studies, which reveal clinically significant symptom reductions and functional improvement in about two-thirds of patients. DBS was well tolerated overall and adverse effects were overwhelmingly transient. Results generally improved for patients implanted more recently, suggesting a 'learning curve' both within and across centers. This is well known from the development of DBS for movement disorders. The main factor accounting for these gains appears to be the refinement of the implantation site. Initially, an anterior-posterior location based on anterior capsulotomy lesions was used. In an attempt to improve results, more posterior sites were investigated resulting in the current target, at the junction of the anterior capsule, anterior commissure and posterior ventral striatum. Clinical results suggest that neural networks relevant to therapeutic improvement might be modulated more effectively at a more posterior target. Taken together, these data show that the procedure can be successfully implemented by dedicated interdisciplinary teams, and support its therapeutic promise.

Vagus nerve stimulation for depression: rationale, anatomical and physiological basis of efficacy and future prospects.

Treatment-resistant depression (TRD) is a major public health concern due to its high costs to society. One of the novel approaches for the treatment of depression is the vagus nerve stimulation (VNS). Therapeutic brain stimulation through delivery of pulsed electrical impulses to the left cervical vagus nerve now has established safety and efficacy as an adjunct treatment for medication-resistant epilepsy and has recently been approved as an adjunct long-term treatment for chronic or recurrent depression. There is considerable evidence from both animal and human neurochemical and neuroimaging studies, that the vagus nerve and its stimulation influence limbic and higher cortical brain regions implicated in mood disorders, providing a rationale for its possible role in the treatment of psychiatric disorders. Clinical studies (open-label and comparator with treatment in naturalistic setting) in patients with TRD have produced promising results, especially when the response rates at longer-term (one- and two-year) follow-up time points are considered. Ongoing research efforts will help determine the place of VNS in the armament of therapeutic modalities available for major depression.

Development and initial validation of a screening tool for Parkinson disease surgical candidates.

As there is currently no standardized assessment tool for evaluating Parkinson disease (PD) patients for deep brain stimulation (DBS), the authors developed the Florida Surgical Questionnaire for Parkinson Disease (FLASQ-PD). Part I of the study was a retrospective analysis of 174 patients presenting for a surgical screening. Part II was a multicenter study to assess the correlation of FLASQ-PD scores. The results of this study suggest that the FLASQ-PD may be a useful triage tool for screening PD patients for DBS surgery.

Radiation and regeneration: behavioral improvement and GDNF expression after Gamma Knife radiosurgery in the 6-OHDA rodent model of hemi-parkinsonism.

BACKGROUND: Recent research has demonstrated that the adult mammalian CNS is capable of regeneration. This regeneration is often initiated as a response to thermal, chemical or mechanical injury. The effects of radiation on the mammalian CNS have also been found to aid in certain regeneration processes. METHOD: In our project we examined the potential therapeutic value of radiation induced regeneration of diseased mammalian rat CNS. Eleven Sprague-Dawley rats with 6-hydroxy-dopamine (6-OHDA) induced hemi-parkinsonism were treated in the Leksell Gamma Knife using a single 4 mm collimator shot targeted to the ipsilateral (parkinsonian) caudate-putamen complex. A maximum dose of 140 Gy was used to create a necrotic lesion. Animals were tested behaviorally using the apomorphine-induced rotational behavior model before and up to 6 months after radiosurgery. Histochemical analysis was performed 2 weeks, 1 month and 4 months after radiosurgery. Histological sections were obtained and immunohistochemistry was performed for glial cell line derived neurotrophic factor (GDNF). FINDINGS: The rotational behavior for 11/11 animals (100%) was found to initially worsen at 2 weeks and 4 weeks after radiosurgery before a statistically highly significant reduction in apomorphine induced rotations was observed at 2, 3, and 4 months after radiosurgery (83% reduction by month four; p < 0.0001). For 2/11 animals the rotational behavior almost disappeared indicating near-abolition of parkinsonian behavior. On histological examination, the lesions were easily identified as areas of necrosis about 4 mm in diameter. The region immediately adjacent to the lesion was found to have highly positive expression of GDNF indicating high activity in dopamine-regenerating processes. INTERPRETATION: In this preliminary study we demonstrated that radiosurgical lesioning with the Gamma Knife into the striatum of hemi-parkinsonian animals resulted in significant behavioral improvement of signs of parkinsonism. Since GDNF expression is tightly linked to the dopaminergic system, we conclude that focused radiation is potentially capable of inducing regeneration of dopaminergic pathways in the adult CNS. Further studies with dose deescalation and molecular biological characterization of the regeneration cascades are necessary to gain access to potential clinical value of our observations.

Acid-related diseases following retrosternal stomach interposition.

BACKGROUND/AIMS: Esophagectomy and reconstruction with retrosternal stomach interposition implies bilateral truncal vagotomy, which supposedly causes gastric functional impairment. METHODOLOGY: Esophagectomy and reconstruction with retrosternal stomach interposition was performed on 15 men (mean age: 58.4 years) and 3 women (mean age: 43.6 years). The stomach was pedicled on the right gastric and right gastroepiploic artery without performing pyloroplasty. The cervical side-to-end anastomosis was sutured manually. The functional results were assessed 2-4 years postoperatively, by determining 24-hour qualitative intragastric pH-measurement, fluoroscopical gastric emptying studies, fasting gastrin levels, and endoscopy with biopsy studies. RESULTS: Endoscopy and biopsy confirmed esophagitis in 12 patients, gastritis in 15 and a gastric ulcer in 1 case. Fluoroscopic examination documented a normal passage of contrast medium in 17, slight impairment in 1 case treated by balloon dilatation of the pylorus. Qualitative intragastric pH-measurement revealed a total pH < 3 in 22.5-98.05% of measuring events (mean: 74.31%) within 24 hours, in 18 cases. Only 4 patients had pH < 3 in less than 50%. Fasting gastrin levels (normal range: 25-110 mU/L) varied from 48.78 mU/L-168.20 (mean: 85.23 mU/L). Only 3 patients had levels > 110 mU/L (maximum: 168.20 mU/L). CONCLUSIONS: Acid-related diseases may also occur after truncal vagotomy and retrosternal stomach interposition. Routine follow-up endoscopy and biopsy studies should be done to prevent inflammatory complications and maintain the patient's quality of life.

Gamma knife surgery for treatment of central neurocytomas. Report of four cases.

The authors investigated the use of gamma knife surgery (GKS) in the treatment of central neurocytoma, a usually benign primary brain tumor of the lateral and third ventricles. Four patients with subtotally resected or recurrent central neurocytomas were retrospectively studied. The prescription isodose was 9 to 13 Gy to the 30 to 50% peripheral isodose line. Pre- and postoperative magnetic resonance (MR) images were compared to determine the volume reduction following GKS. Follow-up review included annual MR imaging and clinical evaluation by a neurosurgeon. Follow-up periods ranged from 12 to 99 months. Marked reduction in tumor size was seen in all four patients; the decrease in tumor volume for each was 48%, 72%, 81%, and 77%, respectively, at the last follow-up review. None of the four patients required additional treatment and none experienced a decline in neurological function during the follow-up period. No complications have been noted in any of these patients to date. Even though there have been few observations and follow-up time has been limited, because of the consistency of the response and the lack of observed side effects, GKS may be the treatment of choice for subtotally resected and recurrent central neurocytomas.

Effect of photodynamic therapy in a multimodal approach for advanced carcinoma of the gastro-esophageal junction.

UNLABELLED: Background and Objective We wanted to determine the role of additional photodynamic therapy in a multimodal approach for the treatment of patients with advanced cancer of the gastro-esophageal junction. Study Design/Materials and Methods We reviewed 53 patients, after endoluminal palliation, with advanced cancer of the gastro-esophageal junction. Combined dilatation and retrograde tumor disobliteration with Nd-YAG laser before photodynamic therapy (PDT), brachyradiotherapy, or both, became necessary in 12 patients. Brachyradiotherapy was carried out in all patients. PDT before brachyradiotherapy was performed in 25 patients. The endoluminal treatment was completed by external beam irradiation in 30 patients (15 cases with PDT and 15 without PDT) with an at least fair performance status. RESULTS: Photodynamic therapy showed a significant difference regarding the mean opening of the tumor stenosis (mean, 6.4 mm; P = 0.0002), the mean decrease in tumor length (3.1 cm; P = 0.00001) and the increase in median survival (13. 8 months; P = 0.001). The combined multimodal approach by using PDT, brachyradiotherapy and external beam irradiation showed a median survival of 16.8 months. However, additional external beam irradiation showed no significant difference (P = 0.11). The rate of severe complications was 5.7%. The mortality rate was 1.9%. CONCLUSION: Photodynamic therapy has been shown to be an effective treatment for palliation of advanced cancer at the gastro-esophageal junction. The use of PDT combined with irradiation was associated with an acceptable survival rate, low rates of complications and reasonable quality of life.

Review of severe osteoradionecrosis treated by surgery alone or surgery with postoperative hyperbaric oxygenation.

We reviewed 41 patients with osteoradionecrosis of the mandible. Each patient was treated by radical resection followed by external beam irradiation. The diagnosis of infected osteoradionecrosis was confirmed clinically, radiologically, and histologically. After operation had failed, 20/41 were given hyperbaric oxygen (HBO) as in 'salvage' treatment. Daily sessions of HBO 2.5 ATA for 60 minutes (mean: 29 sessions) were given. The other 21 patients were treated by operation and antibiotics alone. HBO group (n = 20): The overall success rate for HBO after operation had failed was 13/20. Repeated debridement as first-line treatment followed by postoperative HBO was successful in 12/19. In seven of 19 patients, partial mandibulectomy and microvascular transplantation were required as second-line treatment, and this was successful in five. Primary partial mandibulectomy and microvascular transplantation followed by HBO was successful in 1 patient. Non-HBO group (n = 21): Repeated debridement was successful in 10/11 patients. Partial mandibulectomy was required as second-line treatment in the remaining one. In the other 10, partial mandibulectomy and microvascular transplantation were successful as first-line treatment in four. In the remaining six, further surgical intervention became necessary and were successful for 5-17 months (mean: 13). With a success rate of 13/20, we do not recommend HBO for the treatment of osteoradionecrosis.

Hyperbaric oxygen and photodynamic therapy in the treatment of advanced carcinoma of the cardia and the esophagus.

BACKGROUND AND OBJECTIVE: The photochemical reaction of photodynamic therapy (PDT) depends on the presence of molecular oxygen. Because of anoxic regions in tumor tissue and vascular shutdown during PDT, the efficiency is limited. Therefore, the use of hyperbaric oxygen, which increases the oxygen in tumor tissue, as well as the amount of singlet oxygen, may enhance the efficiency of PDT. STUDY DESIGN/MATERIALS AND METHODS: After diagnostic work-up, photosensitization was carried out with a hematoporphyrin-derivate 2 mg/kg body weight 48 hours before PDT. The light dose was calculated as 300 J/cm of fiber tip. Twenty-three patients were treated by PDT alone and 29 patients received PDT under hyperbaric oxygen at a level of two absolute atmospheric pressures. RESULTS: Improvement regarding dysphagia and stenosis-diameter could be obtained in both treatment arms with no significant difference (P = 0.43 and P = 0. 065, respectively). The tumor length also decreased in both groups and showed a significant difference in favour of the PDT/HBO group (P = 0.002). The mean overall survival was 11.3 months. The mean survival time for the PDT group was 8.7 months and for the PDT/HBO group 13.8 months (P = 0.021). CONCLUSION: According to this pilot study, combined PDT/HBO represents a new approach in the treatment of esophageal and cardia cancer, which appears to have enhanced the efficiency of PDT.

Four-year experience with pleural abrasion using a rotating brush during video-assisted thoracoscopy.

BACKGROUND: Due to the high recurrence rate in primary spontaneous pneumothorax (PSP), surgical therapy is currently a well-accepted method of treating this condition. There is no general agreement about the best time for surgical intervention (i.e., after the first or second episode) or the optimal surgical approach,--i.e., tube thoracocenteses, thoracotomy, or video-assisted thoracoscopy (VATS) with or without pleurectomy or pleurodesis. The aim of this study was to verify the efficacy of VATS and mechanical brush pleurodesis using a rotating electrical brush system. METHODS: We treated 47 patients with PSP between June 1993 and June 1997. Follow-up ranged from 20 to 56 months. There were 38 male and nine female patients with a mean age of 26 years. Emergency thoracocenteses due to tension pneumothorax became necessary in three patients. All patients were treated by VATS and mechanical brush pleurodesis. Wedge resection was done if bullae or blebs were present (68.1%). RESULTS: Operating time was 20-60 min (mean, 35). There were no intraoperative complications and no conversions to conventional surgery. In the first few postoperative days, postoperative pain was controlled with nonsteroidal antirheumatic drugs and additional morphines. Drainage time was 3-7 days (mean, 4). Hospitalization time was 4-8 days (mean, 5). The recurrence rate was 2.1% (one patient). No postoperative bleeding or wound infection occurred in any of our patients. CONCLUSIONS: VATS combined with mechanical brush pleurodesis using the electrical brush system is a highly effective and safe treatment for patients with recurrent primary spontaneous pneumothorax.

Does hyperbaric oxygen enhance the effect of photodynamic therapy in patients with advanced esophageal carcinoma? A clinical pilot study.

BACKGROUND AND STUDY AIMS: Experimental studies have shown that the cytotoxicity of porphyrins and related substances is mediated mainly by singlet oxygen and that hypoxic cells are less affected by porphyrins and light. In a clinical pilot study we assessed the use of photodynamic therapy (PDT) under hyperbaric oxygen (HBO), compared with PDT under normobaric conditions, in patients with advanced esophageal carcinoma. PATIENTS AND METHODS: After diagnostic work-up and staging, photosensitization in all patients was carried out using hematoporphyrine derivate (HpD) (2 mg/kg bodyweight 48 hours prior to PDT). We then applied light at 630 nm (KTP-Nd: YAG laser with DYE box) at dose of 300 J/cm, delivered by a fiber with a radial light-diffusing cylinder (length 1 cm), inserted through the biopsy channel of the endoscope. Of the patients, 14 (12 with stage III cancers, and two with stage IV cancers) were treated by PDT alone, and 17 patients (15 with stage III cancers, and two with stage IV cancers) received PDT under HBO at a level of 2 absolute atmospheric pressures (ATA). Transcutaneous PO2 levels of 500-750 mm Hg under HBO, compared with transcutaneous PO2 levels of 60-75 mm Hg under normobaric conditions, were measured. RESULTS: Improvements regarding dysphagia and stenosis diameter were obtained in both treatment arms with no significant differences (P = 0.36 and 0.14, respectively). The tumor length also decreased in both groups and showed a significant difference in favour of the PDT/ HBO group (P = 0.002). Kaplan-Meier statistics showed median overall survival for the PDT group and the PDT/HBO group as 7.0 and 12 months respectively. The 12-month survival rate was 28.6% for the PDT group and 41.2% for the PDT/HBO group. Logrank test showed a difference in survival in favor of the PDT/HBO group (P = 0.059). No major treatment-related complication occurred, and the 30-day mortality rate was 0%. CONCLUSIONS: Combined PDT/HBO represents a new approach in the treatment of esophageal cancer which, in this pilot study, appears to have enhanced the efficiency of PDT.

Comparison of geometric distortion in digital angiography with and without a correction program. Technical note.

This study was conducted to evaluate the geometric distortion of angiographic images created from a commonly used digital x-ray imaging system and the performance of a commercially available distortion-correction computer program. A 12 x 12 x 12-cm wood phantom was constructed. Lead shots, 2 mm in diameter, were attached to the surfaces of the phantom. The phantom was then placed inside the angiographic localizer. Cut films (frontal and lateral analog films) of the phantom were obtained. The films were analyzed using GammaPlan target series 4.12. The same procedure was repeated with a digital x-ray imaging system equipped with a computer program to correct the geometric distortion. The distortion of the two sets of digital images was evaluated using the coordinates of the lead shots from the cut films as references. The coordinates of all lead shots obtained from digital images and corrected by the computer program coincided within 0.5 mm of those obtained from cut films. The average difference is 0.28 mm with a standard deviation of 0.01 mm. On the other hand, the coordinates obtained from digital images with and without correction can differ by as much as 3.4 mm. The average difference is 1.53 mm, with a standard deviation of 0.67 mm. The investigated computer program can reduce the geometric distortion of digital images from a commonly used x-ray imaging system to less than 0.5 mm. Therefore, they are suitable for the localization of arteriovenous malformations and other vascular targets in gamma knife radiosurgery.

Neurosurgical approaches to intractable obsessive-compulsive disorder.

Although significant progress has been made over the last decade in the treatment of obsessive-compulsive disorder (OCD), approximately 20% of OCD patients remain refractory to nonsurgical therapies, including pharmacologic and cognitive-behavioral therapy. Because a number of neural circuits involving the basal ganglia, thalamus, limbic system, and frontal lobes have been implicated in the pathophysiology of OCD, the need for an effective intervention in these patients has brought the focus on surgical approaches, including cingulotomy and capsulotomy procedures. Unlike free-hand surgical approaches used in the past, current neurosurgical interventions have been greatly enhanced by advances in technology, which allow lesioning to an accuracy of 1 mm. Today's neurosurgical approaches have shown significant benefit in as many as 60% of refractory patients, while preserving personality and cognitive functioning and limiting morbidity. A study of gamma knife capsulotomy conducted at Brown University School of Medicine showed that 40% of patients undergoing two lesioning procedures were much or very much improved 2 years postsurgery. The inherent obstacles to conducting placebo-controlled studies in these severely ill patients mean that further study is required to identify optimal candidates for surgical intervention.

Self-expandable coated stent after intraluminal treatment of esophageal cancer: a risky procedure?

BACKGROUND: Stenting is a well established palliative treatment for stenotic malignant disease of the esophagus. Because of its merely mechanical potential other tumoricidal techniques are often done before stenting. METHODS: We did esophageal stenting in 11 patients (9 men and 2 women) using a self-expanding coated stent system. Three tumors were localized in the proximal, four in the middle, and four in the distal third of the esophagus. In 9 patients tumors were locally or functional nonresectable, 1 patient refused an operation, and 1 had a recurrence after esophagojejunostomy. One patient had had pretreatment by repetitive dilatation and local hyperthermia, 9 had had photodynamic therapy followed by endoluminal iridium 192 high-dose rate brachyradiotherapy, and 1 patient was admitted with esophagotracheal fistula. The interval between the last endoluminal treatment and stent insertion was between 3 and 29 days (mean, 11 days). RESULTS: In 7 patients (63.7%) no complications were observed. Four patients (36.3%) died of major complications within 1 week. Postmortem examination confirmed that the pressure of the fully expanding stent to the esophageal wall caused the rupture. CONCLUSION: The use of self-expanding coated stents in pretreated esophageal tumors is associated with a high risk of perforation due to pressure of the indwelling tube in a less resistant esophageal wall.

Is aggressive surgery in pleural empyema justified?

OBJECTIVE: High risk and a long hospitalization time are often quoted as negative aspects of aggressive surgery in pleural empyema. We did a retrospective analysis evaluating outcome and duration of hospitalization in patients treated according to an aggressive schedule. METHODS: Since 1989 we have treated 101 patients with pleural empyema (72 males, 29 females; mean age 50.3 years, range 11-91 years; 77 metapneumonic empyema, 24 empyema following trauma or abdominal surgery). Sixty-nine patients had had unsuccessful conservative pre-treatment (antibiotics, thorcozentses, drainage/irrigation, VATS). Thirty-one were critically ill patients. In eight cases a seropurulent stage of empyema was present, 17 patients had fibrinous membranes, 30 an organizing stage with and 46 without well identifiable dissection plane. Eighty-five patients proceeded to thoracotomy. Pulmonary abscesses or indurative pneumonia necessitated wedge-resection, lobectomy, or pneumonectomy in 29 cases. In the presence of gross necroses or callosities not amenable to decortication primary open-window thoracostomy (n = 22) was carried out. In six cases a secondary open-window thoracostomy was carried out because of persisting putrid secretion and sepsis persisting after decortication or after drainage. The thoracostomy was closed when clean granulative tissue developed. Sixteen patients underwent only drainage and irrigation because of an early stage or because of a general condition not permitting thoracotomy. RESULTS: Three patients died due to severe sepsis not responding to treatment, one had fatal bleeding from a duodenal ulcer (mortality rate 3.9%). The others were able to resume their preoperative activities. The median duration of hospitalization was 14 days (mean 21.1 days; SEM 1.7 days). CONCLUSION: Aggressive surgery for pleural empyema beyond the seropurulent stage ensures rapid relief from sepsis at a low mortality rate even in very ill patients.