Pharmacokinetics of levobupivacaine with epinephrine in transversus abdominis plane block for postoperative analgesia after Caesarean section.

BACKGROUND: Transversus abdominis plane block is increasingly used for post-Caesarean section analgesia. Cases of toxicity and the limited pharmacokinetic information during pregnancy motivated this study. The objective of the study was to characterise and compare the pharmacokinetics of levobupivacaine with epinephrine in tranversus abdominis plane block, in post-Caesarean section patients and healthy volunteers. METHODS: After approval by the Ethics Committee, we collected data from 12 healthy parturients after elective Caesarean section (Study 1) and data from 11 healthy male volunteers from a previous study (Study 2). Transversus abdominus plane block was performed under ultrasound guidance. The following injectates were used: levobupivacaine 0.25%, 20 ml with epinephrine 5 µg ml-1 (Study 1) per side; 20 ml of the same solution (unilateral block) (study 2). The plasma venous concentration of levobupivacaine was measured serially for 90 min. Pharmacokinetic parameters (volume of distribution, clearance, and absorption half-life) were estimated using a non-linear mixed effects model (NONMEM). Simulation in 1000 patients estimated the maximum concentration and the time to reach it after bilateral transversus abdominis plane block. RESULTS: Venous concentrations were below toxic levels (2.62 mg L-1). Levobupivacaine volume of distribution after Caesarean section was higher than in healthy volunteers [172 L (70 kg)-1 (95% confidence interval: 137-207) vs 94.3 L (70 kg)-1 (95% CI: 62-128); P<0.01]. Clearance and absorption half-life were similar. The simulation showed that maximum levobupivacaine concentration is lower and occurs later in postpartum patients (P<0.01). Postoperative analgesia was effective. CONCLUSIONS: Postpartum women reached relatively low plasma concentrations of levobupivacaine after transversus abdominal plane block given a volume of distribution 80% higher than volunteers, which could confer a greater margin of safety. CLINICAL TRIAL REGISTRATION: NCT02852720.

Dexmedetomidine metabolic clearance is not affected by fat mass in obese patients.

BACKGROUND: Obesity has been associated with reduced dexmedetomidine clearance, suggesting impaired hepatic function or reduced hepatic blood flow. The aim of this study was to clarify the effect of obesity in dexmedetomidine metabolic clearance. METHODS: Forty patients, ASA I-III, 18-60 yr old, weighing 47-126 kg, scheduled for abdominal laparoscopic surgery, were enrolled. Anaesthetic agents (propofol, remifentanil, and dexmedetomidine) were dosed based on lean body weight measured by dual X-ray absorptiometry. Serial venous samples were drawn during and after dexmedetomidine infusion. A pharmacokinetic analysis was undertaken using non-linear mixed-effect models. In the modelling approach, the total body weight, lean body weight, and adjusted body weight were first tested as size descriptors for volumes and clearances. Hepatic blood flow, liver histopathology, liver enzymes, and gene expression of metabolic enzymes (UGT2B10 and UGT1A4) were tested as covariates of dexmedetomidine metabolic clearance. A decrease in NONMEM objective function value (ΔOFV) of 3.84 points, for an added parameter, was considered significant at the 0.05 level. RESULTS: A total of 637 dexmedetomidine serum samples were obtained. A two-compartmental model scaled to measured lean weight adequately described the dexmedetomidine pharmacokinetics. Liver blood flow was a covariate for dexmedetomidine clearance (ΔOFV=-5.878). Other factors, including fat mass, histopathological damage, and differential expression of enzymes, did not affect the dexmedetomidine clearance in the population studied (ΔOFV<3.84). CONCLUSIONS: We did not find a negative influence of obesity in dexmedetomidine clearance when doses were adjusted to lean body weight. Liver blood flow showed a significant effect on dexmedetomidine clearance. CLINICAL TRIAL REGISTRATION: NCT02557867.

Fluorescence and Cerenkov luminescence imaging. Applications in small animal research.

This review addresses small animal optical imaging (OI) applications in diverse fields of basic research. In the past, OI has proven to be cost- and time-effective, allows real-time imaging as well as high-throughput analysis and does not imply the usage of ionizing radiation (with the exception of Cerenkov imaging applications). Therefore, this technique is widely spread - not only geographically, but also among very different fields of basic research - and is represented by a large body of publications. Originally used in oncology research, OI is nowadays emerging in further areas like inflammation and infectious disease as well as neurology. Besides fluorescent probe-based contrast, the feasibility of Cerenkov luminescence imaging (CLI) has been recently shown in small animals and thus represents a new route for future applications. Thus, this review will focus on examples for OI applications in inflammation, infectious disease, cell tracking as well as neurology, and provides an overview over CLI.

Potential clinical predictors of outcome after postoperative radiotherapy of non-small cell lung cancer.

AIM: The aim of this analysis was to investigate the impact of tumour-, treatment- and patient-related cofactors on local control and survival after postoperative adjuvant radiotherapy in patients with non-small cell lung cancer (NSCLC), with special focus on waiting and overall treatment times. PATIENTS AND METHODS: For 100 NSCLC patients who had received postoperative radiotherapy, overall, relapse-free and metastases-free survival was retrospectively analysed using Kaplan-Meier methods. The impact of tumour-, treatment- and patient-related cofactors on treatment outcome was evaluated in uni- and multivariate Cox regression analysis. RESULTS: No statistically significant difference between the survival curves of the groups with a short versus a long time interval between surgery and radiotherapy could be shown in uni- or multivariate analysis. Multivariate analysis revealed a significant decrease in overall survival times for patients with prolonged overall radiotherapy treatment times exceeding 42 days (16 vs. 36 months) and for patients with radiation-induced pneumonitis (8 vs. 29 months). CONCLUSION: Radiation-induced pneumonitis and prolonged radiation treatment times significantly reduced overall survival after adjuvant radiotherapy in NSCLC patients. The negative impact of a longer radiotherapy treatment time could be shown for the first time in an adjuvant setting. The hypothesis of a negative impact of longer waiting times prior to commencement of adjuvant radiotherapy could not be confirmed.

Laser-assisted resection of a giant pulmonary chondrohamartoma--a case report.

A rare case of a giant pulmonary chondromatous hamartoma (15 cm, 1350 g) resected by a new laser system (Nd:YAG, 1318 nm, 40 W) is presented. The laser management of a hamartoma resection--the largest reported to date in the literature--is presented here.

Laser resection of lung parenchyma--a new technical and clinical approach.

The introduction of a new 1318 nm wavelength Nd:YAG laser has created new possibilities in lung parenchyma surgery. The potentially curative surgical resection of pulmonary metastases in suitably selected cases had been recognized slowly. Using the new laser technology a greater number of patients can now offered salvage surgery. This paper reviews the history of surgical management of pulmonary metastases, development of new laser technology, conventional and extended indications for pulmonary metastasectomy and use of laser in thoracic surgery.

Resection of multiple lung metastases--where are the limits?

Multiple lung metastases present a serious and challenging problem with increasing incidence for thoracic surgeons. In the lung metastasis management a significant role belongs to laser lung-parenchyma-saving resection. This parenchyma saving technique allows a removal of significant higher number of lung nodules in comparison to conventional techniques (stapler, clamp resection). Performing the lung metastasectomy by this manner, the only remaining question is the limitation of this technique. In this retrospective study, the results after Nd:YAG Laser (1318 nm, 40 Watt) interventions are being presented, the limitations of this technique are being discussed (Tab. 3, Fig. 4, Ref. 9).

The role of an exposed loop in the alpha2 domain in the mouse MHC class I H-2Dd molecule for recognition by the monoclonal antibody 34-5-8S and the NK-cell receptor Ly49A.

Natural killer (NK) cells express major histocompatibility complex (MHC) class I-specific inhibitory receptors. The region mediating the protective effect of the MHC class I molecule H-2Dd (Dd), recognized by the inhibitory receptor Ly49A, has been mapped to the alpha1/alpha2 domains. Here we have focused on an exposed loop in the N-terminal part of the alpha2 domain, which constitutes a major structural motif that differs between Dd (strong binding to Ly49A) and Db (weak binding to Ly49A at best). We mutated the residues 103, 104 and 107 in Dd to the corresponding amino acids in Db. The Dd mutant molecule retained the ability to be stabilized by a Dd-binding peptide. However, the mutation totally abolished the recognition by the conformational dependent monoclonal antibody (MoAb) 34-5-8S, known to inhibit the interaction between Dd and Ly49A. In addition, there was a marked impairment of the binding to Ly49A as evaluated by the ability of tetramers of the Dd mutant molecule to bind to Ly49A-transfected reporter cells and spleen cells. These results demonstrate that the introduced changes at positions 103, 104 and 107 directly or indirectly affect the epitopes for the MoAb 34-5-8S and the Ly49A receptor.

[Palliative surgery for primary and secondary thoracic malignancies]. / Chirurgische Palliation im Thoraxbereich bei primären und sekundären Malignomen.

Palliative thoracic surgical interventions aim to assure or to improve quality of life. They encompass surgical correction of vital complications, treatment of symptoms that limit daily activities, and prophylactic interventions to reduce symptoms and improve prognosis. Interventions are based on statistically proved results as well as on profound clinical experience in oncologic surgery. Because palliation does not intent to cure, such operations require precise patient information and inclusion of the respective patient in decision making. Operability depends on patient general condition and extent of the procedure. If tumor is resected local radicality is the principle goal also in palliative situations, which is adapted to each individual case, especially in the context of multimodal treatment strategies. One of the main indications of palliative thoracic surgery in pulmonary metastasectomy. Using the new laser technology loss of parenchyma is minimal and the rate of lobectomies is reduced from 25% to 4%. With mortality and morbidity of less than 1% the 5-year survival after complete metastasectomy is more than 30%. Tumors of the thoracic wall cause pain and tend to exulcerate; due to their obvious presence they induce anxiety. Their removal and subsequent plastic surgery of the chest wall defect therefore makes sense also in advanced stages. Palliative and curative surgery is one of the pillars in plurimodal treatment of mediastinal tumors, besides its role in obtaining tissue for histologic diagnosis. Thoracoscopic talc pleurodesis has a success rate of more than 90% in malignant effusions if the lung is fully expandable.

MHC class I recognition by NK receptors in the Ly49 family is strongly influenced by the beta 2-microglobulin subunit.

NK cell recognition of targets is strongly affected by MHC class I specific receptors. The recently published structure of the inhibitory receptor Ly49A in complex with H-2Dd revealed two distinct sites of interaction in the crystal. One of these involves the alpha1, alpha2, alpha3, and beta2-microglobulin (beta2m) domains of the MHC class I complex. The data from the structure, together with discrepancies in earlier studies using MHC class I tetramers, prompted us to study the role of the beta2m subunit in MHC class I-Ly49 interactions. Here we provide, to our knowledge, the first direct evidence that residues in the beta2m subunit affect binding of MHC class I molecules to Ly49 receptors. A change from murine beta2m to human beta2m in three different MHC class I molecules, H-2Db, H-2Kb, and H-2Dd, resulted in a loss of binding to the receptors Ly49A and Ly49C. Analysis of the amino acids involved in the binding of Ly49A to H-2Dd in the published crystal structure, and differing between the mouse and the human beta2m, suggests the cluster formed by residues Lys3, Thr4, Thr28, and Gln29, as a potentially important domain for the Ly49A-H-2Dd interaction. Another possibility is that the change of beta2m indirectly affects the conformation of distal parts of the MHC class I molecule, including the alpha1 and alpha2 domains of the heavy chain.

Histologically proven extrinsic allergic alveolitis with severe obstructive pulmonary emphysema

Anamnesis: 61-year old man with progressive shortness of breath on exercise. Cough and expectoration during the last 6 years. - Exposure: Driver of cereals, massive exposure to mouldy and pest contaminated grains. Gave up his profession in 1979 due to dyspnea with short (2-3 h) latency after exposure. Since 1980 intermittent exposure during occasional jobs; renewed symptomatology. Aspergillus fumigatus detected on agar plates inoculated with material from wet areas in bathroom and kitchen. - Clinical symptoms: Barely audible vesicular breathing, barrel-shaped thorax, inspiratory-intercostal retraction. - Bodyplethysmography: Obstructive pulmonary emphysema with FEV1 0.8 l, TLC 7.8 l, RV/TLC relation 67%. - Precipitin-detection: Significantly increased IgG against Fusarium. Other moulds including Aspergillus: negative; thermophilic actinomycetes: negative; pigeon and chicken: negative; Ouchterlony with native material from patients flat: negative. - CT including HR-CT: Bilateral-substantial emphysema, no bullae, no ground glass-opacity, no signs for interstitial lung diseases, no mediastinal enlargement of lymph nodes. - Alpha-1-Antitrypsin: 1.67 to 2.3 g/l (normal range), phenotype M1. - Histology: In resected material from right-side lung-volume-resection detection of pulmonary emphysema as well as lymphocyte infiltration and numerous epitheloid cell granulomas with Langhans'giant cells without caseation assessed as residues of an exogenous allergic alveolitis. - Conclusion: In a patient with lung volume reduction surgery due to severe emphysema histologically a persistent exogenous allergic alveolitis was detected, which might have caused the emphysema.

The interferon-inducible 204 gene, a member of the Ifi 200 family, is not involved in the antiviral state induction by IFN-alpha, but is required by the mouse cytomegalovirus for its replication.

To examine whether Ifi 200 genes are involved in antiviral state induction by IFNs we expressed mutant forms capable of inactivating the endogenous p204 and analyzed replication of both RNA and DNA viruses following IFN-alpha treatment. Inactivation of p204 does not impair replication of vesicular stomatitis virus, encephalomyocarditis virus, ectromelia virus, and herpes simplex virus 1 and does not alter an IFN-alpha induced antiviral state. By contrast, in cells lacking functional p204, mouse cytomegalovirus (MCMV) replication is strongly inhibited and is not further modulated by IFN-alpha. These results suggest that p204, a member of the Ifi 200 gene family, is not involved in the IFN-alpha-induced antiviral activity against some RNA or DNA viruses, but is required by MCMV for its replication.

Extensive multiple and lobe-sparing pulmonary resections with the Nd: YAG laser and a new wavelength of 1318 nm.

AIMS: Analysing the results of extensive parenchymal resections in 110 patients we want to demonstrate the safe usage and the superiority of the second Nd: YAG laser wavelength (1318 nm) which shows significantly better lung tissue determinants. METHODS: Between 3/96 and 11/97, 110 patients (66 men and 44 women, mean age 60 years) were integrated prospectively in three groups and underwent pulmonary surgery with the Nd: YAG laser of the 1318 nm wavelength. 78 patients had suspected lung metastases of known primary malignancies (group 1); 20 patients with poor lung function had peripheral T1 or T2 lung primaries (group 2) and 12 patients had multiple pulmonary nodules but unknown malignancies (group 3). RESULTS: In group 1 we resected 353 nodules or 4.6 nodules per patient, between 5 and 60 nm. Although 41% of all lesions were deep-seated and only 28% solitary, it was in 97.5% possible to perform precision resections. In two patients (2.5%) lobectomy was necessary which demonstrates a drastic decrease of the lobectomy rate--reported between 20 and 30% in the literature. There was no mortality in all groups, and only two complications were treated conservatively. DISCUSSION: The technical improvements in this special laser (1318 nm) allow extensive parenchymal resections and should make the long-discussed advantages of lasers in open lung surgery applicable to a broad clinical usage.

RT1-U: identification of a novel, active, class Ib alloantigen of the rat MHC.

In common with other mammalian species, the laboratory rat (Rattus norvegicus) expresses MHC class I molecules that have been categorized as either classical (class Ia) or nonclassical (class Ib). This distinction separates the class Ia molecules that play a conventional role in peptide Ag presentation to CD8 T cells from the others, whose function is unconventional or undefined. The class Ia molecules are encoded by the RT1-A region of the rat MHC, while the RT1-C/E/M region encodes up to 60 other class I genes or gene fragments, a number of which are known to be expressed (or to be expressible). Here we report upon novel MHC class Ib genes of the rat that we have expression cloned using new monoclonal alloantibodies and which we term RT1-U. The products detected by these Abs were readily identifiable by two-dimensional analysis of immunoprecipitates and were shown to be distinct from the class Ia products. Cellular studies of these molecules indicate that they function efficiently as targets for cytotoxic killing by appropriately raised polyclonal alloreactive CTL populations. The sequences of these class Ib genes group together in phylogenetic analysis, suggesting a unique locus or family. The combined serological, CTL, and sequence data all indicate that these products are genetically polymorphic.

Co-evolution of rat TAP transporters and MHC class I RT1-A molecules.

The genes for rat major histocompatibility complex (MHC) class I molecules are associated either with those for the A allele of the transporter associated with antigen processing (TAP-A), which can transport peptides with basic carboxy-terminal residues, or with those for TAP-B, which cannot [1-5]. To explore whether these associations have a functional basis, we compared the sequences of 13 rat MHC class la RT1-A cDNAs from nine MHC haplotypes. Of seven TAP-A- linked RT1-A molecules, six possess strongly acidic F pockets, and these bind a high proportion of peptides with basic carboxy-terminal residues. The F pockets of TAP-B-linked molecules, by contrast, were more basic. Furthermore, we identified six positions at the 'righthand end' of the peptide-binding groove, at which a majority of TAP-B-linked molecules diverge from the consensus sequence for class la molecules whereas, at these positions, all the TAP-A-linked molecules reflect the consensus sequence. Our results suggest that the linked rat class la and TAP genes have co-evolved to maximize the supply of appropriate peptides to the presenting molecules.

Pancreatitis crónica cefálica / Cephalic chronic pancreatitis

La mayoría de las pancreatitis producen un agrandamiento glandular difuso, sin embargo la ecografía (ECO) y la tomografía axial computada (TC) pueden mostrar masas inflamatorias focales, indistinguibles del adenocarcinoma ductal. La colangiografía retrógrada endoscópica (CPER) puede poner en evidencia obstrucción completa del conducto de Wirsung y de la vía biliar haciendo el diagnóstico erróneo de carcinoma de páncreas. Se estudiaron 3 pacientes con sospecha de enfermedad pancreática que fueron examinados mediante ECO, TC y CPER. Dos de las pacientes fueron sometidas a cirugía mientras que a la paciente restante se le realizó una punción biopsia percutánea. Se concluye que las masas inflamatorias del páncreas no siempre pueden ser distinguidas de los carcinomas mediante los diferentes métodos por imágenes. La clínica del paciente puede ser la ayuda pero no siempre existen los antecedentes de alcoholismo. La punción biopsia dirigida por ECO o TC establece el diagnóstico

Pancreatitis crónica cefálica / Cephalic chronic pancreatitis

La mayoría de las pancreatitis producen un agrandamiento glandular difuso, sin embargo la ecografía (ECO) y la tomografía axial computada (TC) pueden mostrar masas inflamatorias focales, indistinguibles del adenocarcinoma ductal. La colangiografía retrógrada endoscópica (CPER) puede poner en evidencia obstrucción completa del conducto de Wirsung y de la vía biliar haciendo el diagnóstico erróneo de carcinoma de páncreas. Se estudiaron 3 pacientes con sospecha de enfermedad pancreática que fueron examinados mediante ECO, TC y CPER. Dos de las pacientes fueron sometidas a cirugía mientras que a la paciente restante se le realizó una punción biopsia percutánea. Se concluye que las masas inflamatorias del páncreas no siempre pueden ser distinguidas de los carcinomas mediante los diferentes métodos por imágenes. La clínica del paciente puede ser la ayuda pero no siempre existen los antecedentes de alcoholismo. La punción biopsia dirigida por ECO o TC establece el diagnóstico (AU)