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.

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.

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.

The X-ray structure of the DNA-binding domain from the Saccharomyces cerevisiae cell-cycle transcription factor Mbp1 at 2.1 A resolution.

The structure of the DNA-binding domain of the Saccharomyces cerevisiae cell-cycle transcription factor Mbp1 has been solved using the multiwavelength anomalous diffraction (MAD) technique on crystals of selenomethionyl protein and refined at 2.1 A resolution. The molecule is globular, consisting of a twisted, six-stranded beta-barrel that is packed against a loose bundle of four alpha-helices. Two of the beta-strands in combination with two of the helices form a structure characteristic of the DNA-binding motif found in the CAP family of helix-turn-helix transcription factors. In Mbp1, this beta2/alpha2 motif is associated with regions of both positive electrostatic potential and sequence conservation within the Mbp1/Swi4 family, suggesting a role in DNA-binding in these proteins. A combination of structural and biochemical data further indicate a similarity to HNF3gamma/fork head, a member of the family of "winged" helix-turn-helix proteins. We propose a model for DNA-binding involving a recognition helix in the major groove, phosphodiester backbone interactions through the beta-hairpin and further base and/or phosphate interactions mediated by a C-terminal, positively charged loop.

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.

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.

Moderate dose intraoperative and external beam radiotherapy for locally recurrent rectal carcinoma.

BACKGROUND AND PURPOSE: Late adverse effects (i.e. neuropathy, chronic bowel obstruction) limit the effective dose given in intraoperative radiotherapy (IORT) and external beam radiotherapy (EBRT). Initial results of a multi-modality treatment approach using moderate dose IORT and moderate dose EBRT are presented. PATIENTS AND METHODS: Thirty-one consecutive patients with recurrent rectal carcinomas had IORT and EBRT after complete (R0, n = 14) or incomplete resection (R1, n = 9; R2, n = 8). The mean [ORT dose was 13.7 Gy (range 12-20 Gy) supplemented with an EBRT dose of 41.4 Gy. Twenty-two patients had preoperative EBRT and 22 patients had concomitant chemotherapy (5-FU, Leucovorine). RESULTS: After a median follow-up of 28 months, 16 patients had re-recurrent disease and 11 patients had died. Nine patients failed locally (four in-field, four marginal and one anastomotic re-recurrence), three combined with distant metastasis, resulting in overall and IORT infield local control rates of 71% and 87%, respectively. Distant metastases alone were found in seven patients. The 4-year overall and relapse-free survival rates were 58% and 48%, respectively. After incomplete resection the local failure rate increased (R0 21%, R1/2 35%) and the 4-year relapse-free survival rate decreased significantly (29% versus 71%) due to a markedly increased distant metastasis rate (53% versus 7%). Acute and late toxicities were not increased. CONCLUSION: The combination of moderate dose IORT and EBRT is a safe and efficacious component in a multi-modality treatment approach.

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.

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%.

Methodology-dependent variation in documentation of outcome predictors in out-of-hospital cardiac arrest.

OBJECTIVE: To identify variation in outcome predictor documentation in out-of-hospital cardiac arrest associated with two different methods of data collection: concurrent questioning of personnel following a resuscitation attempt and archival report review. METHODS: All patients > or = 18 years old who had out-of-hospital cardiac arrests, verified using the New York City 911 telephone system, between October 1, 1990, and April 1, 1991, were eligible for inclusion. The authors reviewed the first 200 cases of presumed primary cardiac arrest involving a resuscitation attempt among 3,243 consecutive ambulance call reports for cardiac arrest occurring during the study period. This archival data set was compared with data for the same 200 cases gathered through direct interview of field personnel by trained paramedics. The two data sets had been compiled independently by different individuals, using the same data collection instrument, which conformed to the Utstein template. RESULTS: Comparison of the data obtained from ambulance records with the data obtained from interviews of prehospital personnel revealed several areas of variance. Of note was a significantly lower proportion of bystander-witnessed ventricular fibrillation (VF) in the data set gathered from written reports (7% vs 18%; 95% CI for the difference 4-18%; p = 0.001). CONCLUSION: differences in methods of collection of out-of-hospital cardiac arrest data are associated with a more than twofold variation in the reported incidences of witnessed cardiac arrests manifesting as VF. Methodology-dependent variation in this important "denominator" may produce substantially different estimates of survival within the same cohort of patients.

[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.

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.