Search

About half of the neurons in the parabrachial nucleus (PB) that are activated by CO2 are located in the external lateral (el) subnucleus, express calcitonin gene-related peptide (CGRP), and cause forebrain arousal. We report here, in male mice, that most of the remaining CO2-responsive neurons in the adjacent central lateral (PBcl) and Kölliker-Fuse (KF) PB subnuclei express the transcription factor FoxP2 and many of these neurons project to respiratory sites in the medulla. PBclFoxP2 neurons show increased intracellular calcium during wakefulness and REM sleep and in response to elevated CO2 during NREM sleep. Photo-activation of the PBclFoxP2 neurons increases respiration, whereas either photo-inhibition of PBclFoxP2 or genetic deletion of PB/KFFoxP2 neurons reduces the respiratory response to CO2 stimulation without preventing awakening. Thus, augmenting the PBcl/KFFoxP2 response to CO2 in patients with sleep apnea in combination with inhibition of the PBelCGRP neurons may avoid hypoventilation and minimize EEG arousals.The parabrachial nucleus contains separate populations of neurons that respond to elevated CO2 with EEG arousal and increased breathing. Here we report that the parabrachial respiratory neurons express FoxP2 and are required for respiratory responses to elevated CO2. [ABSTRACT FROM AUTHOR]

Copyright of Zeitschrift für Gerontologie und Geriatrie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

During obstructive sleep apnea, elevation of CO2 during apneas contributes to awakening and restoring airway patency. We previously found that glutamatergic neurons in the external lateral parabrachial nucleus (PBel) containing calcitonin gene related peptide (PBelCGRP neurons) are critical for causing arousal during hypercapnia. However, others found that genetic deletion of serotonin (5HT) neurons in the brainstem also prevented arousal from hypercapnia. To examine interactions between the two systems, we showed that dorsal raphe (DR) 5HT neurons selectively targeted the PBel. Either genetically directed deletion or acute optogenetic silencing of DRSert neurons dramatically increased the latency of mice to arouse during hypercapnia, as did silencing DRSert terminals in the PBel. This effect was mediated by 5HT2a receptors which are expressed by PBelCGRP neurons. Our results indicate that the serotonergic input from the DR to the PBel via 5HT2a receptors is critical for modulating the sensitivity of the PBelCGRP neurons that cause arousal to rising levels of blood CO2. Dorsal raphe 5HT(DRSert) neurons regulate arousal from hypercapnia by their projections to the neurons in the external lateral parabrachial nucleus (PBel) that are glutamatergic and also express calcitonin gene related peptide (PBelCGRP). The DRSert input to the PBel modulates the arousal system to rising levels of blood CO2, and may be mediated by 5HT2a receptors on the PBelCGRP neurons. [ABSTRACT FROM AUTHOR]

Introduction: Whereas in the adult population 5-Aminolevulinic acid (5-ALA) fluorescence guidance has been widely accepted for improving the extent of tumor resection, the application in children remains an off-label use. Even though most pediatric study protocols require a complete resection for improving outcome parameters, only few pediatric patients have been operated with fluorescence guidance, and it remains questionable, whether and which pediatric tumors show useful fluorescence. We present casuistic reports of application of 5-ALA in children collected from three different neurosurgical departments. Patients and methods: In children with suspected malignant intracerebral tumor or recurrence, individual informed consent was obtained in each case from the parents. 5-ALA was administered according to the adult protocol, with 20 mg/kg, 2 h before induction of anesthesia. We retrospectively analyzed 18 patients (13 male, 5 female; age 3-18 years), using the intraoperative neurosurgical protocol, the postoperative MRI results, and the follow-up clinical examinations. Results: The use of 5-ALA fluorescence guidance proved to be safe in our group of pediatric patients. Fluorescence guidance was most useful for recurrent glioblastoma resection. Medulloblastoma tissue displayed fluorescence only inconsistently, and most pilocytic astrocytoma remained without staining. Ganglioglioma showed partial staining in the central tumor areas, without allowing the use for circumferent resection. Conclusion: The off-label use of 5-ALA fluorescence guidance in pediatric patients appears to be most useful in recurrent high-grade gliomas. Fluorescence accumulation in other pediatric brain tumor entities is not predictable and should be evaluated in future clinical studies before being integrated into the current treatment protocols. [ABSTRACT FROM AUTHOR]

The cancer-testis antigen NY-ESO-1 is a potential target antigen for immune therapy expressed in a subset of patients with multiple myeloma. We generated chimeric antigen receptors (CARs) recognizing the immunodominant NY-ESO-1 peptide 157-165 in the context of HLA-A*02:01 to re-direct autologous CD8+ T cells towards NY-ESO-1+ myeloma cells. These re-directed T cells specifically lysed NY-ESO-1157-165/HLA-A*02:01-positive cells and secreted IFNγ. A total of 40% of CCR7− re-directed T cells had an effector memory phenotype and 5% a central memory phenotype. Based on CCR7 cell sorting, effector and memory CAR-positive T cells were separated and CCR7+ memory cells demonstrated after antigen-specific re-stimulation downregulation of CCR7 as sign of differentiation towards effector cells accompanied by an increased secretion of memory signature cytokines such as IL-2. To evaluate NY-ESO-1 as potential target antigen, we screened 78 bone marrow biopsies of multiple myeloma patients where NY-ESO-1 protein was found to be expressed by immunohistochemistry in 9.7% of samples. Adoptively transferred NY-ESO-1-specific re-directed T cells protected mice against challenge with endogenously NY-ESO-1-positive myeloma cells in a xenograft model. In conclusion, re-directed effector- and central memory T cells specifically recognized NY-ESO-1157-165/ HLA-A*02:01-positive cells resulting in antigen-specific functionality in vitro and in vivo. [ABSTRACT FROM AUTHOR]

We report on some implications of the theory of turbulence developed by V. Yakhot (Phys. Rev. E 57(2):1737, ). In particular we focus on the expression for the scaling exponents ζ. We show that Yakhot's result contains three well known scaling models as special cases, namely K41, K62 and the theory by V. L'vov and I. Procaccia (Phys. Rev. E 62(6):8037, ). The model furthermore yields a theoretical justification for the method of extended self-similarity (ESS). [ABSTRACT FROM AUTHOR]

Background: An outcome assessment was performed of patients with unresectable colorectal liver metastases (CRLM) treated in second or third line with floxuridine (FUDR)-based hepatic artery infusion (HAI). Methods: Twenty-three patients who were pretreated with systemic (immuno)chemotherapy received FUDR-HAI alone or combined with systemic chemotherapy. We reviewed patient charts and our prospective patient database for survival and associated risk factors. Results: Patients received FUDR-HAI for unresectable CRLM from January 2000 to September 2010. Twelve patients (52%) received concurrent systemic chemotherapy. Median overall survival (OS), progression-free survival (PFS), and hepatic PFS were 15.6 months (range, 2.5-55.7 months), 3.9 months (range, 0.7-55.7 months), and 5.5 months (range, 1.6-55.7 months), respectively. The liver resection rate after HAI was 35%. PFS was better in patients undergoing secondary resection than in patients without resection (hazard ratio [HR] 0.21; 95% confidence interval [95% CI] 0.07-0.66; P = 0.0034), while OS showed a trend toward improvement (HR 0.4; 95% CI 0.13-1.2; P = 0.09). No differences were observed in OS ( P = 0.69) or PFS ( P = 0.086) in patients who received FUDR-HAI alone compared with patients treated with combined regional and systemic chemotherapy. No statistically significant differences were seen in patients previously treated with one chemotherapy line compared with patients treated with two lines. Presence of extrahepatic disease was a negative risk factor for PFS (liver-only disease: HR 0.03; 95% CI 0.0032-0.28; P < 0.0001). Toxicities were manageable with dose modifications and supportive measures. Conclusions: FUDR-HAI improves PFS and results in a trend toward improved OS in selected patients able to undergo liver resection after tumor is downsized. [ABSTRACT FROM AUTHOR]

The International Breast Implant Registry (IBIR) was founded in 2002 under the auspices of the International Plastic, Reconstructive, and Aesthetic Surgery Foundation (IPRAF), the International Confederation for Plastic, Reconstructive, and Aesthetic Surgery (IPRAS), and the European and International Committee for Quality Assurance, Medical Technologies, and Devices in Plastic (EQUAM) on the basis of continuous discussion about the safety and compatibility of different breast implants. The IBIR aims to integrate and replace the already existing national breast implant registries. It also is assumed that the European Parliament, the Food and Drug Administration, and international organizations of plastic and aesthetic surgeons will postulate obligatory international breast implant registration. Currently, IBIR is in a pilot phase with the goal of understanding data collection issues and concerns in various countries whereby the data entered to date will be completely available in the final version. A well-established global registry represents an important tool of quality assurance. By publishing their experiences in applying the registry, the authors aim to encourage more plastic and aesthetic surgeons to submit their cases to the registry and thus enhance its value as a successful and powerful device. [ABSTRACT FROM AUTHOR]

We report the generation of a chimeric monoclonal antibody (ch806) with specificity for an epitope on the epidermal growth factor receptor (EGFR) that is different from that targeted by all other anti-EGFR therapies. Ch806 antibody is reactive to both de2-7 and overexpressed wild-type (wt) EGFR but not native EGFR expressed in normal tissues at physiological levels. Ch806 was stably expressed in CHO (DHFR-/-) cells and purified for subsequent characterisation and validated for use in preliminary immunotherapy investigations. Ch806 retained the antigen binding specificity and affinity of the murine parental antibody. Furthermore, ch806 displayed enhanced antibody-dependent cellular cytotoxicity against target cells expressing the 806 antigen in the presence of human effector cells. Ch806 was successfully radiolabelled with both iodine-125 and indium-111 without loss of antigen binding affinity or specificity. The radioimmunoconjugates were stable in the presence of human serum at 37°C for up to 9 days and displayed a terminal half-life (T1/2ß) of approximately 78?h in nude mice. Biodistribution studies undertaken in BALB/c nude mice bearing de2-7 EGFR-expressing or amplified EGFR-expressing xenografts revealed that125I-labelled ch806 failed to display any significant tumour retention. However, specific and prolonged tumour localisation of'111In-labelled ch806 was demonstrated with uptake of 31%ID?g-1 and a tumour to blood ratio of 5?:?1 observed at 7 days postinjection. In vivo therapy studies with ch806 demonstrated significant antitumour effects on established de2-7 EGFR xenografts in BALB/c nude mice compared to control, and both murine 806 and the anti-EGFR 528 antibodies. These results support a potential therapeutic role of ch806 in the treatment of suitable EGFR-expressing tumours, and warrants further investigation of the potential of ch806 as a therapeutic agent.British Journal of Cancer (2005) 92, 1069-1077. doi:10.1038/sj.bjc.6602470 www.bjcancer.com Published online 15 March 2005 [ABSTRACT FROM AUTHOR]

Copyright of Der Urologe A is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Immunotherapy of cancer is still in the early stages of development although almost a century has passed since initial attempts were made to stimulate the immune system in order to destroy malignant cells. Historically, a variety of specific and non-specific immunostimulatory strategies have been administered with only modest clinical success. However, recent advances in tumour immunology, most notably the identification of new tumour antigens and the better understanding of antigen processing and presentation to avoid or break immune tolerance, have paved the way for the development of a variety of novel and specific vaccine approaches. The most important and widely used are whole-cell vaccines, dendritic-cell-based immunotherapy and peptide vaccines. The first wave of clinical trials has revealed that, in general, such vaccination strategies are safe. However, clear examples of clinical responses, especially in conjunction with vaccine-induced immune responses, are still rare. Most clinical trials are too small to allow for comments on the efficacy, and the cohort of patients studied is too heterogeneous with regard to immune status. Therefore, standardised techniques for the accurate assessment of the individual immune phenotype before and during the trial are needed to allow for the identification of the sub-group of patients who will respond favourably to treatment. The precise definition of immune parameters in these patients will then lead the way for optimised treatment procedures that might even be beneficial for a larger group of cancer patients. [ABSTRACT FROM AUTHOR]

Substantial progress has been made in vaccine development in recent years for the treatment of malignant diseases. New technologies have fostered the identification of potentially immunogenic tumour antigens that can be used to activate the patient's immune system to specifically recognize and destroy human tumour cells. More detailed insights into the process of intracellular protein degradation, processing and cell surface presentation have allowed immunogenic peptide domains to be identified that can be used in vaccine trials. Still a matter of intensive debate is the question of the most optimal presentation of tumour-derived proteins or peptides to the immune system to achieve a maximum response. In this area, major progress has been made by using dendritic cell or even naked DNA-based vaccines. The generation of new tools such as HLA-tetramer complexes now allows researchers to monitor more closely the expansion of peptide-specific T cells under the process of vaccination. On the basis of these advances, a couple of vaccine trials have been performed that have increased our knowledge of vaccine development and provided indications that the concept of tumour-specific vaccination might be valid. However, we are still at the beginning of this process and should always remember that only well-designed, prospective clinical trials can define the optimal use of tumour vaccines in oncology. [ABSTRACT FROM AUTHOR]

Copyright of Monatsschrift Kinderheilkunde is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The availability of monoclonal antibodies with well-defined specificities to lymphoma-associated antigens promises to open new therapeutic opportunities in the treatment of patients with non-Hodgkin's lymphoma. Monoclonal antibodies against lineage-specific surface markers such as CD19, CD20 or CD22 have been generated and employed in native or modified forms in clinical phase 1/11 trials. Modified versions such as toxin-conjugated antibodies or antibodies with dual specificities (bispecific antibodies) were introduced to enhance the cytotoxicity of monoclonal antibodies since native antibodies were not able to induce long-lasting remissions in patients with advanced disease although responses were seen and side-effects were usually mild. Future efforts should concentrate on patients with minimal residual disease employing genetically engineered antibody fragments. [ABSTRACT FROM AUTHOR]

The effects of sodium citrate supplementation to improve aspartic acid supply in a 5-year-old girl with argininosuccinate lyase deficiency were studied over a period of 5 years under constant and total parenteral nutrition. Daily increasing doses of sodium citrate (0-8 mmol/kg) were continuously infused i.v.. Her standard therapy with arginine hydrochloride (4 mmol/kg/day) and sodium benzoate (200 mg/kg/day) was continued. Serum citrulline concentrations were reduced by citrate supplementation (161.8-41.7 mumol/l). Correspondingly serum concentrations of argininosuccinate and its anhydrides rose (270-458 mumol/l), positively correlated with the doses of sodium citrate. Renal elimination of argininosuccinate did not change measurably. There was no improvement in plasma ammonia concentration, which remained between 88 and 136 mumol/l. A long-standing hepatomegaly did not improve. The patient developed a significant alkalosis with blood pH-values increasing up to 7.55. The alkalosis lead to a reduction in renal ammonium elimination by at least 5.3 mmol/kg per day; the portion of ammonium-nitrogen decreased from 54.2% to finally 9% of total urinary nitrogen. Nevertheless total urinary nitrogen elimination, as measured by pyrochemiluminescence, improved by 24.5% during the 5 days and rose from 2065 mg nitrogen/day to 2570 mg/day. This improvement could not be explained by the metabolites determined and corresponded with an increase in chemically undefined nitrogen excretion, which rose from 0% to 65.9% of total urinary nitrogen. Further investigations are necessary to elucidate the nature of these unexplained nitrogen-containing compounds. CONCLUSION. Sodium citrate supplementation improved renal nitrogen elimination in a patient with argininosuccinate lyase deficiency in the observation period of 5 days by up to 24.5%. [ABSTRACT FROM AUTHOR]

Copyright of Monatsschrift Kinderheilkunde is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Monatsschrift Kinderheilkunde is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The purpose of this study was to assess the value of morphometric data on conventional radiography and CT predicting the presence and degree of pulmonary hypertension and to assess the reversibility after surgery. On preoperative X-ray films and CT scans of 50 patients with pulmonary hypertension secondary to chronic thromboembolism, we measured the cardiothoracic ratio, basal diameter, length of cardiac contact to sternum, pulmonary trunk, right and left descending pulmonary artery, and the septum angle. These data were correlated with pulmonary arterial pressure. In 14 X-ray patients and 18 CT patients, with follow-up after surgical thromboendarterectomy the reversibility of these changes was assessed. A dilated pulmonary trunk was the most common abnormality (96% each on X-ray and CT). Pulmonary arteries were dilated on X-ray in 40% (right) and 14% (left), and on CT in 92% (right) and 96% (left). The best correlation with mean arterial pressure was found measuring the pulmonary trunk on CT (r = 0.43, p < 0.01). After surgery, reversibility was most significant for the pulmonary trunk on CT (p < 0.0001). In patients with chronic pulmonary embolism, pulmonary hypertension can best be predicted by assessing the diameter of the pulmonary trunk both on X-ray and CT. No close correlation is present between the extent of any parameter and the level of pulmonary pressure. [ABSTRACT FROM AUTHOR]

Bispecific monoclonal antibodies (bi-mAb), directed against a tumor-associated antigen and the CD3 or CD28 antigen on T lymphocytes, induce activation of resting T lymphocytes and target-specific tumor cell lysis. We now show that both necrosis and apoptosis contribute to T-cell-mediated tumor cell destruction. Even though T cells up-regulate FAS/APO-1 expression upon bi-mAb stimulation, FAS/APO-1-mediated apoptosis does not contribute to bi-mAb-mediated destruction of Hodgkin’s cells. CD8+ lymphocytes were the most potent effectors of bi-mAb-mediated cytotoxicity and had the highest levels of mRNA coding for perforin and granzyme A and B. Ca2+-complexing agents, which abrogate perforin activity, led to decreased levels of necrosis, while inhibition of granzyme activity in effector or target cells had a similar effect on apoptosis. Granzyme-mediated apoptosis critically dependent on the proliferative state of the target cells, while perforin-induced necrosis was not cell-cycle-dependent. Our results underline the importance of the expression levels of perforin and granzymes in the effector T cells and of the proliferative state of the target cells in bi-mAb-mediated apoptosis and necrosis of tumor cells. [ABSTRACT FROM AUTHOR]

The effects of five nematocidal drugs (levamisole HCl, metrifonate, fenbendazole, mebendazole, and ivermectin) on the nematode Anguillicola crassus, pathogenic in eels and recently introduced in Europe, were tested under in vivo conditions. The resulting tissue alterations were studied by means of light and electron microscopy. It was found that levamisole and metrifonate were most effective in a freshwater bath (1 mg/l) for 24 h. The 50% lethal dose of levamisole was 250 mg/l per 24 hours, whereas that of metrifonate was only 10 mg/l per 2 hours. Morphological studies of the nematodes showed that there was no drug-specific reaction. In general, the hypodermis, the cytoplasmic portions of the muscle cells, and the intestinal wall were most intensively damaged, leading to an irreversible vacuolation and finally to death. [ABSTRACT FROM AUTHOR]

A letter to the editor about the dominant cancer-testis antigen by humoral immune responses in patients with multiple myeloma is presented.

A recombinant fusion protein of colon carcinoma binding A33 single chain antibody with cytosine deaminase displayed specific antigen binding and enzyme activity in surface plasmon resonance and is catalytic activity assay. In vitro, it selectively increased the toxicity of 5-FC to A33 antigen-positive cells by 300-fold, demonstrating the potency of this ADEPT strategy. [ABSTRACT FROM AUTHOR]

A recombinant fusion protein of colon carcinoma binding A33 single chain antibody with cytosine deaminase displayed specific antigen binding and enzyme activity in surface plasmon resonance and is catalytic activity assay. In vitro, it selectively increased the toxicity of 5-FC to A33 antigen-positive cells by 300-fold, demonstrating the potency of this ADEPT strategy. [ABSTRACT FROM AUTHOR]

Copyright of Monatsschrift Kinderheilkunde is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)