Pupillary response to percutaneous auricular vagus nerve stimulation in alcohol withdrawal syndrome: A pilot trial.

BACKGROUND: Autonomic symptoms in alcohol withdrawal syndrome (AWS) are associated with a sympathetic-driven imbalance of the autonomic nervous system. To restore autonomic balance in AWS, novel neuromodulatory approaches could be beneficial. We conducted a pilot trial with percutaneous auricular vagus nerve stimulation (pVNS) in AWS and hypothesized that pVNS will enhance the parasympathetic tone represented by a reduction of pupillary dilation in a parasympatholytic pharmacological challenge. METHODS: Thirty patients suffering from alcohol use disorder, undergoing AWS, and stable on medication, were recruited in this open-label, single-arm pilot trial with repeated-measure design. Peripheral VNS (monophasic volt impulses of 1 msec, alternating polarity, frequency 1 Hz, amplitude 4 mV) was administered at the left cymba conchae for 72 h, followed by pupillometry under a tropicamide challenge. We assessed craving with a visual analog scale. We used pupillary mean as the dependent variable in a repeated-measures ANOVA (rmANOVA). RESULTS: A repeated-measures ANOVA resulted in a significant difference for pupillary diameter across time and condition (F(2,116) = 27.97, p < .001, ηp2 > .14). Tukey-adjusted post hoc analysis revealed a significant reduction of pupillary diameter after pVNS. Alcohol craving was significantly reduced after pVNS (p < .05, Cohen's d = 1.27). CONCLUSION: Our study suggests that pVNS activates the parasympathetic nervous system in patients with acute AWS, and that this activation is measurable by pupillometry. To this end, pVNS could be beneficial as a supportive therapy for AWS. Potential confounding effects of anti-craving treatment should be kept in mind.

Association between umbilical cord vitamin D levels and adverse neonatal outcomes.

OBJECTIVE: We investigated the associations between cord blood concentration of 25-hydroxyvitamin D [25(OH)D], neonatal outcomes, and the risk of hospitalization during the first year of life. METHODS: A total of 402 newborn infants and their mothers were prospectively enrolled and divided in four groups according to season of the year. We determined 25(OH)D serum concentrations from maternal-neonatal pairs at delivery by electrochemiluminescence immunoassay. Cut-offs at 25, 50, and 75 nmol/L defined vitamin D status, corresponding to deficiency, insufficiency, and sufficiency, respectively. Crude odds ratio (cOR) and 95% confidence intervals (CI) were estimated using logistic regression. RESULTS: Vitamin D severe deficiency (i.e., <25 nmol/L) was present in 18% of newborns. Cord blood severe deficiency was associated with an increased risk of preterm birth (cOR 3.6, 95% CI: 1.1-12.2), neonatal respiratory distress syndrome (cOR 5.9, 95% CI: 1.1-33.2), and increased risk of hospitalization during the first year of life because of acute respiratory infection (cOR 3.9, 95% CI: 1.4-10.6) or acute gastroenterocolitis (cOR 5.2, 95% CI: 1.4-19.1). CONCLUSION: Cord blood vitamin D deficiency is associated with increased risk of preterm birth, neonatal respiratory distress syndrome, and hospitalization during the first year of life.

Iterative probabilistic voxel labeling: automated segmentation for analysis of The Cancer Imaging Archive glioblastoma images.

BACKGROUND AND PURPOSE: Robust, automated segmentation algorithms are required for quantitative analysis of large imaging datasets. We developed an automated method that identifies and labels brain tumor-associated pathology by using an iterative probabilistic voxel labeling using k-nearest neighbor and Gaussian mixture model classification. Our purpose was to develop a segmentation method which could be applied to a variety of imaging from The Cancer Imaging Archive. MATERIALS AND METHODS: Images from 2 sets of 15 randomly selected subjects with glioblastoma from The Cancer Imaging Archive were processed by using the automated algorithm. The algorithm-defined tumor volumes were compared with those segmented by trained operators by using the Dice similarity coefficient. RESULTS: Compared with operator volumes, algorithm-generated segmentations yielded mean Dice similarities of 0.92 ± 0.03 for contrast-enhancing volumes and 0.84 ± 0.09 for FLAIR hyperintensity volumes. These values compared favorably with the means of Dice similarity coefficients between the operator-defined segmentations: 0.92 ± 0.03 for contrast-enhancing volumes and 0.92 ± 0.05 for FLAIR hyperintensity volumes. Robust segmentations can be achieved when only postcontrast T1WI and FLAIR images are available. CONCLUSIONS: Iterative probabilistic voxel labeling defined tumor volumes that were highly consistent with operator-defined volumes. Application of this algorithm could facilitate quantitative assessment of neuroimaging from patients with glioblastoma for both research and clinical indications.

Primary and locally recurrent retroperitoneal soft-tissue sarcoma: local control and survival.

AIM: To evaluate local control for long-term prognosis in retroperitoneal soft-tissue sarcoma (primary tumors (PT) and local recurrence (LR)). METHODS: A total of 110 patients underwent surgery between 1988 and 2002. Prospectively gathered clinicopathological data were analyzed. Kaplan-Meier estimations and Cox regression analyses were performed. RESULTS: Resectability was 90%, being comparable for PT (n=71) and LR (n=39). Morbidity, mortality, blood loss, and operation time did not differ for PT or LR (24% vs. 31%, p=0.41; 7.0% vs. 5.1%, p=1.0; 1000 ml vs. 1500 ml, p=0.17; 240 min vs. 255 min, p=0.13). Hospitalization was comparable in both groups (median, 12 days (PT) and 13 days (LR)). Follow-up was 89 months (median, IQR 37-112 months). Local 3- and 5-year control rates after complete resection of PT were 66% and 59% (19% and 9% for LR, p<0.001). The mean number of operations were 1.4 for PT and 2.4 for LR (p=0.0047). The 5-year survival rates after complete resection were 51% for PT and 43% for LR (p=0.39). The 5-year survival rates were 65%, 4%, and 0% for complete resection, incomplete resection, and exploration, respectively (p<0.001). Multivariate analysis showed high-grade and blood loss with a poor prognosis. CONCLUSIONS: Comparable resectability rates and perioperative outcome were observed for surgery of PT and LR. Consequent reoperation leads to respectable long-term survival rates after resection of LR. The prognosis in retroperitoneal sarcomas varies significantly according to resectability, grade and blood loss.

Indolent stage IE non-Hodgkin's lymphoma of the orbit: results after primary radiotherapy.

AIMS: Primary non-Hodgkin's lymphoma (NHL) of the orbit is uncommon, representing approximately 8% of extranodal NHLs. Twenty-two patients with indolent stage IE NHL were reviewed retrospectively to analyze the outcome and late effects of primary local radiotherapy. MATERIALS AND METHODS: The median age at first diagnosis was 63.5 years (range 24-82 years). Extranodal mucosa-associated lymphoid tissue lymphoma (n = 15) was the most common histological subtype of NHL, followed by follicular (n = 6) and lymphoplasmacytic lymphoma (n = 1). Radiotherapy was performed using a linear accelerator. The median radiation dose was 40 Gy (range 30-46 Gy). None of the patients received chemotherapy before irradiation. The follow-up period was 62 months (range 8-136 months). RESULTS: A complete response was achieved in all patients. The 5-year local control rate was 100%. Distant relapse occurred in 2 patients, resulting in a 5-year distant relapse-free survival rate of 88%. The 5-year overall survival rate was 89%; there were no lymphoma-related deaths. No serious acute complications (grade 3/4) were observed. Grade 1/2 late effects were documented in 44% of patients. Grade 3 complications (cataract: 2, dryness: 2) were observed in 4 patients (18%). CONCLUSIONS: Indolent early stage orbital NHL can be controlled with local radiotherapy. Morbidity is low. Regular follow-up examinations are necessary to detect rare cases of distant relapse.

[Intraoperative extracorporeal irradiation and replantation in local treatment of primary malignant bone tumors]. / Intraoperative extrakorporale Irradiation und Replantation (IEIR) in der lokalen Behandlung primär maligner Knochentumoren.

In 13 patients with primary malignant bone tumors (10 Ewing's sarcoma, 1 parosteal osteosarcoma, 1 adamantinoma recurrence, and 1 MFH) local therapy was performed as intraoperative extracorporeal irradiation and replantation (IEIR) of the involved bone segment (5 tibia, 2 femur, and 6 pelvis). Of the 13 patients (69%), 9 are alive at the time of the follow-up (5 CDF, 4 AWM(treated)) and 4 patients died of disease (DOD). Up to now during the follow-up of 32 months (6-57), no local recurrence was observed in the replanted bone segments. The complication rate was very high (18 complications in 11 of the 13 patients, including 6 cases with complication V degrees according to Ruggieri with loss of the reconstruction). The typical complication is severe local infection necessitating removal of the replant. In cases of mechanical failure, the replanted segment could mostly be preserved by surgical revision and autologous bone grafting. If serious complications can be managed or avoided, functional results can be achieved. IEIR must be seen as an extraordinary reconstruction procedure in cases where established procedures such as endoprosthesis, biological reconstructions, or rotationplasties cannot be used or are refused by the patient.

[Intraoperative radiotherapy as part of the treatment concept of soft tissue sarcomas]. / Die intraoperative Strahlentherapie im Behandlungskonzept von Weichteilsarkomen.

The therapy of soft tissue sarcomas is not uniform. The goal of treatment for soft tissue sarcomas is surgical resection with negative microscopic margins. Other therapy options are pre-, intra-, or postoperative radiotherapy as well as neoadjuvantor adjuvant chemotherapy with different drugs, systemic or under local perfusion of the limb. If a margin-free surgical resection is not possible, intraoperative radiation therapy (IORT) offers the possibility for treatment of sites at high risk for local recurrence. The goal of this collaborating study of the Orthopedic University Hospital of Heidelberg and the department of Radio-Oncology of the University Hospital of Heidelberg is to observe the influence of IORT on the rate of local recurrence, complications, metastases, and survival in another wise unchanged tumor management. From 1960 to 1998,78 patients were treated for soft tissue sarcomas; 26 of 78 patients underwent intraoperative radiation and 52 patients were treated without intraoperative radiation. We found a recurrence rate of 15% in the IORT group and 29% in the non-IORT group. No difference for survival or distant recurrence was found, also no difference in early postoperative complication rate, but a higher rate of late complications after IORT (34% vs 7%) was remarkable. We think intraoperative radiation allows better local control and for that reason IORT is integrated into our therapeutic concept. Its influence on survival and distant metastases needs further investigations.

The anti-inflammatory sesquiterpene lactone parthenolide suppresses CD95-mediated activation-induced-cell-death in T-cells.

Apoptosis is a morphologically distinct form of cell death involved in many physiological and pathological processes. The death receptor CD95 (APO-1/Fas) and its ligand (L) CD95L are critically involved in activation-induced-cell-death (AICD) of activated T-cells. Here we show that the anti-inflammatory sesquiterpene lactone parthenolide derived from the European traditional herb-medicine feverfew and many Mexican India medicinal plants suppresses expression of the CD95L and CD95 at the mRNA levels, thus, preventing T-cells from AICD. We demonstrate that parthenolide blocks NF-kappaB binding to the two NF-kappa binding sites of the CD95L promoter and suppresses promoter activity upon T-cell activation. Aberrant expression of CD95 and, particularly CD95L is dangerous and may lead to severe diseases. Our study indicates that parthenolide supports T-cell survival by down-regulating the CD95 system, at least in part, and, therefore, may have therapeutic potential as a new anti-apoptotic substance against AICD in T-cells.

[Improving local control in patients with aggressive fibromatosis by combined surgery and radiotherapy]. / Verbesserung der lokalen Kontrolle bei Patienten mit aggressiver Fibromatose durch die Kombination von Chirurgie und Strahlentherapie.

INTRODUCTION: The purpose of this retrospective analysis is to evaluate whether the combination of surgery and radiation therapy in patients with aggressive fibromatosis influences the therapeutic outcome. METHOD: Clinical, radiological and pathological results of 23 consecutive cases with histologically proven aggressive fibromatosis were retrospectively analyzed. The median follow-up was 59 months. RESULTS: Twelve patients received surgery alone for their first treatment, 10 patients had a combination of surgery and radiotherapy and 1 patient had radiochemotherapy. Of 23 patients 14 (63%) had one or more local recurrences and 9 (39%) were recurrence-free. The patients received a total of 50 treatments: 29/50 (58%) treatments were followed by a local recurrence and 21/50 (42%) were without relapse. Twenty-nine treatments with local recurrence consisted of 25/29 (86%) surgical treatments, 3/29 (10%) combinations of surgery and radiation therapy, and 1/29 (3%) radiochemotherapy. Of the patients who had only surgery for their first treatment, after one year 8 of 12 (66%) and after 5 years all patients had a local recurrence. In the group with surgery and radiotherapy, there was no recurrence after 1 year and 1 recurrence after 5 years (p = 0.0001). CONCLUSION: We recommend a complete tumor resection, without mutilating the patient. Radiation therapy in combination with surgery in contrast to surgery alone is an efficient treatment option for reducing local recurrence.

Daily patient set-up control in radiation therapy by coded light projection.

Advances in conformal radiation therapy to control disease via dose escalation are challenged by set-up uncertainties. Recently, techniques have been developed to use surface features to evaluate the patient's position and correct it where necessary. The aim of this study was to use the patient's surface as a tool for daily set-up control and monitoring. We use a surface scanner based on the projection of coded light to receive--in a daily routine--a large amount of surface points which enables us to register the CT-based planning data with the patients current position. By superimposing current and planned volumes, a volume of congruency was obtained. An error below 1 mm was considered acceptable. In cases where set-up was not satisfactory a map of the surface comparison was evaluated showing the areas of missing alignment. According to this information a manual repositioning was performed. This procedure was repeated until the error was acceptable. No more then 3 repetitions where necessary to obtain an acceptable result. The whole procedure including registration, calculation and visualization took about 20 sec for one repetition. The use of structured light projection in the daily set-up control and monitoring proved to be a noninvasive, easy, quick, inexpensive and reliable solution.

Intraoperative radiotherapy for gastrointestinal cancer.

Local recurrence following potentially curative tumor resection is a major problem in patients with gastrointestinal cancer. To augment surgical excision and to avoid the disadvantages of external beam irradiation, intraoperative radiotherapy (IORT) has been applied to primary and recurrent gastrointestinal cancer, both with curative intent and for palliation. There is ample evidence that the combination of radical surgery and IORT can improve local control. Whether this eventually can translate into improved overall survival has not yet been studied in adequately powered randomized and controlled trials.

Intraoperative radiotherapy for primary and locally recurrent soft tissue sarcoma: morbidity and long-term prognosis.

INTRODUCTION: Soft tissue sarcoma has a high risk of local recurrence. Therefore, extensive surgical resection has been combined with radiotherapy to improve long-term results. Because external beam radiation doses may be limited by adjacent radiosensitive tissue, intraoperative boost radiation has been devised to achieve a higher total radiation dose in combination with external beam radiotherapy. We report our experience with this multimodal approach for primary and recurrent soft tissue sarcoma. METHODS: Clinical and pathological data were extracted from a prospective data base including all patients with a diagnosis of soft tissue sarcoma treated at the Department of Surgery, University of Heidelberg between 1988 and 1999. Intraoperative radiotherapy dosages were 12-15 Gy for the extremities and 15-18 Gy for the trunk and the retroperitoneum. Additional external beam radiotherapy was given at 40 Gy, whenever possible. RESULTS: Between 1988 and 1999, a total of 251 patients with primary or recurrent soft tissue sarcoma of the extremities, the trunk or the retroperitoneum were treated. The mean (+/- SD) age of 136 men and 115 women was 53+/-16 years. Five of 251 patients died post-operatively, giving a mortality rate of 2.0%. Intraoperative radiotherapy (IORT) was used in 92 patients (37%). Surgical complications were more frequent in IORT patients (30 of 92; 33%) compared to non-IORT patients (36 of 159; 23% P=0.1). Infectious complications were significantly more frequent in patients receiving IORT (P=0.03). Two hundred and four patients were macroscopically tumour-free (R0, R1 resection). For these patients multivariate analysis identified grading (relative risk (RR) 3.1-6.6; P<0.001), age (over 55 years; (RR) 1.8: P<0.008) and tumour location in the retroperitoneum (RR 2.2; P<0.004) as independently associated with recurrence-free survival. The use of IORT (P<0.02) reduced the relative risk of death or recurrence by 40% (RR 0.6; P<0.02). Sex, primary vs. recurrent tumour, T classification and R-status (R0 vs. R1) were not significantly related to recurrence-free survival. CONCLUSIONS: In this prospective, non-randomized study of soft tissue sarcoma IORT was associated with a higher rate of infectious complications, but the the risk of death or recurrence was reduced by 40%.

Congested traffic states in empirical observations and microscopic simulations

We present data from several German freeways showing different kinds of congested traffic forming near road inhomogeneities, specifically lane closings, intersections, or uphill gradients. The states are localized or extended, homogeneous or oscillating. Combined states are observed as well, like the coexistence of moving localized clusters and clusters pinned at road inhomogeneities, or regions of oscillating congested traffic upstream of nearly homogeneous congested traffic. The experimental findings are consistent with a recently proposed theoretical phase diagram for traffic near on-ramps [D. Helbing, A. Hennecke, and M. Treiber, Phys. Rev. Lett. 82, 4360 (1999)]. We simulate these situations with a continuous microscopic single-lane model, the "intelligent driver model," using empirical boundary conditions. All observations, including the coexistence of states, are qualitatively reproduced by describing inhomogeneities with local variations of one model parameter. We show that the results of the microscopic model can be understood by formulating the theoretical phase diagram for bottlenecks in a more general way. In particular, a local drop of the road capacity induced by parameter variations has essentially the same effect as an on-ramp.

Non-infectious lung complications are closely associated with chronic graft-versus-host disease: a single center study of incidence, risk factors and outcome.

Non-infectious lung complications (NILC) are frequent, influencing morbidity and mortality of patients after allogeneic BMT. Although the term NILC encompasses a number of different entities, an association with GVHD has been noted for almost all of them. Our study was directed towards assessing the incidence and risk factors for developing NILC, as well as the response to treatment and long-term outcome. Forty (14.7%) out of 272 patients surviving for more than 3 months after allogeneic BMT, developed lung complications fulfilling the criteria for NILC. The evaluation was based on clinical investigation, radiologic imaging, lung function tests, broncho-alveolar lavage and biopsies. Risk factors were assessed by univariate and multiple statistical regression models, where chronic GVHD proved to be the only significant risk factor for the development of NILC (P = 0.011). In three patients NILC developed in direct association with donor lymphocyte infusions. The majority of patients responded well to treatment with corticosteroids and immunosuppressive drugs. NILC had no adverse effect on survival. The frequency of NILC was low in autologous (5%) as compared with allogeneic transplants (14.7%) but this difference was not statistically significant. Bone Marrow Transplantation (2000) 25, 1263-1268.

Characterization of the DNA-binding domains from the yeast cell-cycle transcription factors Mbp1 and Swi4.

The minimal DNA-binding domains of the Saccharomyces cerevisiae transcription factors Mbp1 and Swi4 have been identified and their DNA binding properties have been investigated by a combination of methods. An approximately 100 residue region of sequence homology at the N-termini of Mbp1 and Swi4 is necessary but not sufficient for full DNA binding activity. Unexpectedly, nonconserved residues C-terminal to the core domain are essential for DNA binding. Proteolysis of Mbp1 and Swi4 DNA-protein complexes has revealed the extent of these sequences, and C-terminally extended molecules with substantially enhanced DNA binding activity compared to the core domains alone have been produced. The extended Mbp1 and Swi4 proteins bind to their cognate sites with similar affinity [K(A) approximately (1-4) x 10(6) M(-)(1)] and with a 1:1 stoichiometry. However, alanine substitution of two lysine residues (116 and 122) within the C-terminal extension (tail) of Mbp1 considerably reduces the apparent affinity for an MCB (MluI cell-cycle box) containing oligonucleotide. Both Mbp1 and Swi4 are specific for their cognate sites with respect to nonspecific DNA but exhibit similar affinities for the SCB (Swi4/Swi6 cell-cycle box) and MCB consensus elements. Circular dichroism and (1)H NMR spectroscopy reveal that complex formation results in substantial perturbations of base stacking interactions upon DNA binding. These are localized to a central 5'-d(C-A/G-CG)-3' region common to both MCB and SCB sequences consistent with the observed pattern of specificity. Changes in the backbone amide proton and nitrogen chemical shifts upon DNA binding have enabled us to experimentally define a DNA-binding surface on the core N-terminal domain of Mbp1 that is associated with a putative winged helix-turn-helix motif. Furthermore, significant chemical shift differences occur within the C-terminal tail of Mbp1, supporting the notion of two structurally distinct DNA-binding regions within these proteins.

Pediatric ambulance utilization in a large American city: a systems analysis approach.

BACKGROUND: Research on utilization of ambulances by pediatric patients lacks an objective, reproducible tool for the evaluation of patterns of ambulance use by both the providers and the users of this resource. OBJECTIVES: 1) To develop an objective, diagnosis-based measure of appropriateness of ambulance utilization. 2) To use the measure to evaluate whether Municipal Ambulance Service dispatchers assign ambulances appropriately, and whether parents/caretakers request ambulances appropriately. STUDY DESIGN: 1) Development of the pediatric ambulance need evaluation (PANE) tool: The consensus of an expert panel was used to assign patients arriving by ambulance to three levels of prehospital transport need based upon their ultimate hospital discharge diagnoses, and were as follows: required advanced life support ambulance (ALS); required basic life support ambulance (BLS); required a less acute mode of transport (LAT). 2) Assessment of appropriateness of ambulance assignments by EMS call-receiving operators (CRO) and of ambulance requests by parents/caretakers: Comparison of actual type of ambulance assigned and of need for ambulance, using the PANE tool and hospital admission rates as gold standards. DATA COLLECTION: Level of prehospital transport provided (ALS vs BLS), ultimate ED diagnosis, and ED disposition (admission vs discharge) was collected for each patient from information abstracted from the prehospital and ED records. SETTING: Bellevue Hospital Center and Harlem Hospital Center, two level I trauma centers in New York City, both with Pediatric Emergency Departments staffed 24 hours a day by attending physicians and residents. PATIENT SELECTION: Consecutive sample of 2633 patients, birth to 18 years of age, who arrived to either hospital by ambulance as primary transports from the field over a one-year period. RESULTS: 1) Development of PANE tool: At Bellevue Hospital, 7% of ED visits arrived by ambulance; at Harlem Hospital, 5% arrived by ambulance. Using these ambulance arrivals, 215 diagnoses were identified for inclusion in the PANE tool. An expert panel categorized each diagnosis as requiring ALS, BLS, or LAT, with a high level of interobserver agreement (weighted kappa = 0.793). As a measure of external validity of the PANE, admission rates were highest in the ALS group, next highest in the BLS group, and lowest in the LAT group (chi2 for trend, P < 0.05). 2) Assessment of ambulance assignments and requests: According to the PANE tool, the sensitivity of dispatcher assignment of ALS ambulances was 72 %. Therefore, 28 % of patients who required an ALS ambulance received BLS care. 50% of patients assigned to an ALS ambulance did not require that level of care, and 1/3 of these were categorized by the PANE as not requiring an ambulance at all. CONCLUSIONS: The PANE tool compared favorably to admission rates as a measure of the severity of illness of patients arriving by ambulance. Applying the PANE tool, we conclude that the majority of requests for ambulances are appropriate, and that the majority of the time dispatchers were able to dispatch the appropriate level of care. However, there is room for significant improvement in utilization of ambulances, and tools like the PANE will be useful in achieving this goal.

Structural and functional architecture of the yeast cell-cycle transcription factor swi6.

The structural and functional organisation of Swi6, a transcriptional regulator of the budding yeast cell cycle has been analysed by a combination of biochemical, biophysical and genetic methods. Limited proteolysis indicates the presence of a approximately 15 kDa N-terminal domain which is dispensable for Swi6 activity in vivo and which is separated from the rest of the molecule by an extended linker of at least 43 residues. Within the central region, a 141 residue segment that is capable of transcriptional activation encompasses a structural domain of approximately 85 residues. In turn, this is tightly associated with an adjacent 28 kDa domain containing at least four ankyrin-repeat (ANK) motifs. A second protease sensitive region connects the ANK domain to the remaining 30 kDa C-terminal portion of Swi6 which contains a second transcriptional activator and sequences required for heteromerisation with Swi4 or Mbp1. Transactivation by the activating regions of Swi6 is antagonised when either are combined with the central ankyrin repeat motifs. Hydrodynamic measurements indicate that an N-terminal 62 kDa fragment comprising the first three domains is monomeric in solution and exhibits an unusually high frictional coefficient consistent with the extended, multi-domain structure suggested by proteolytic analysis.