Sentinel-Lymph-Node-Mapping beim Adenokarzinom des Kolons verbessert nicht die Genauigkeit des Tumorstagings

ZusammenfassungZiel: In dieser Studie sollten die Wirksamkeit von Sentinel-Lymph-Node-Mapping bei Patienten mit intraperitonealem Kolonkarzinom bestimmt und ein Algorithmus zur Vorhersage eines möglichen Überlebensvorteils unter Verwendung Sentinel-Node-Mapping und Lymphknoten-Ultrauntersuchungstechniken favorisierender Best-Case-Einschätzungen entwickelt werden.Methodik: 41 Patienten mit intraperitonealem Kolonkarzinom, die sich einer Kolektomie mit kurativer Zielsetzung unterzogen, wurden prospektiv untersucht. Nach Mobilisation von Kolon und Mesenterium wurden 1–2 ml des Farbstoffs Isosulfanblau subserös um den Tumor herum injiziert. Die ersten blaugefärbten Lymphknoten wurden als Sentinel Nodes (Wächterknoten) identifiziert. Weitere Knoten wurden vom Pathologen routinemäßig durch manuelle Präparation des Mesenteriums erkannt. Alle Knoten wurden routinemäßig durch histologische Untersuchung mittels Hämatoxylin-Eosin-Färbung aufgearbeitet. Um einen Algorithmus zur Vorhersage des möglichen Überlebensvorteils durch Sentinel-Node-Mapping und Lymphknoten-Ultrauntersuchungstechniken zu entwickeln, wurden Annahmen auf der Basis von Literaturdaten postuliert. Jede Tendenz war auf den Erfolg der Techniken gerichtet.Ergebnisse: Drei von 41 Patienten (7%) wurde keine Farbe injiziert, und sie wurden von der weiteren Analyse ausgeschlossen. Das Krankheitsstadium der übrigen 38 Patienten verteilte sich wie folgt: Stadium I: n = 10 (26%); Stadium II: n = 15 (39%); Stadium III: n = 11 (29%); Stadium IV: n = 2 (5%). Mindestens ein Sentinel Node wurde bei 30 von 38 Patienten (79%) identifiziert. Die mittlere Anzahl erkannter Wächterknoten lag bei zwei (Streuung ein bis drei). Die mittlere insgesamt gewonnene Anzahl an Lymphknoten betrug 14 (Streuung sieben bis 45). Bei 26 von 38 Patienten (68%) waren alle Knoten negativ. Sentinel Nodes und Nonsentinel Nodes waren bei zwei von 38 Patienten (5%) positiv. Bei einem von 38 Patienten (3%) waren Sentinel Nodes die einzigen positiven Lymphknoten. Bei neun von 38 Patienten (24%) waren Sentinel Nodes negativ und Nonsentinel Nodes positiv. Folglich wäre Sentinel-Node-Mapping nur für 3% möglicherweise von Nutzen gewesen, versagte aber in 24% der Patienten unserer Untersuchung bei der genauen Erkennung von Lymphknotenmetastasen. Um einen Algorithmus zur Berechnung des Überlebensvorteils zu entwickeln, trafen wir folgende Annahmen: Kombination des Krankheitsstadiums I und II (0,5); Anteil des Materials, bei dem durch Anwendung histologischer Untersuchung mittels Hämatoxylin-Eosin-Färbung das Stadium zu niedrig eingestuft worden war und das bei differenzierterer Analyse verborgene positive Knoten enthalten könnte (0,15); Anteil von okkulten positiven Knoten, die durch Sentinel-Node-Mapping entdeckt wurden (0,9); sowie Überlebensvorteil durch Chemotherapie (0,33). Somit läge der Anteil der Patienten, die von Sentinel-Lymph-Node-Mapping und Lymphknoten-Ultrauntersuchungstechniken profitierten, bei 0,02 (2%).Schlussfolgerungen: Sentinel-Node-Mapping mit Isosulfanblau-Färbung und Routineaufarbeitung entnommener Knoten verbessert die Genauigkeit des Stagings bei Patienten mit intraperitonealem Kolonkarzinom nicht. Sogar bei Anwendung von Best-Case-Annahmen ist der Prozentsatz von Patienten, die möglicherweise vom Sentinel-Lymph-Node-Mapping profitieren könnten, klein.Übersetzter Nachdruck aus Diseases of the Colon & Rectum 2005;48:80–5. DOI 10.1007/s10350-0795-5     

Influence of acid-pepsin secretion on gastric emptying of solids in humans: studies with cimetidine.

The commonly accepted model for gastric emptying suggests that the 'antral mill' is responsible for the triturition and subsequent emptying of solid food from the stomach. Little is known about the contribution to solid emptying made by other digestive mechanisms such as acid-pepsin secretion. We have investigated the effect of inhibiting gastic secretion on the rate at which a solid test meal emptied from the stomach. Using a radiolabelled beefburger, we performed paired gammacamera studies on consecutive days in 10 fasted, healthy volunteers to compare gastric emptying of the test meal with and without oral cimetidine (400 mg 1 hour before the test, 800 mg at the start of the meal). Inhibition of acid-pepsin secretion by cimetidine was associated with an appreciable delay in the rate of emptying of the burger from the stomach (T50 cimetidine 187 (16) min (mean (SEM); T50 no cimetidine 146 (15) min; p less than 0.01, paired t test). This delay was related to a change in the slope of the emptying profile and was not associated with a prolonged lag phase. These results may be explained by the relative achlorhydria and reduced pepsin activity induced by cimetidine impairing the breakdown of solid food into particles small enough to leave the stomach.     

Role of the proximal and distal stomach in mixed solid and liquid meal emptying.

The role of the proximal and distal stomach in the emptying of solids and liquids from the stomach remains unclear. We have used a dual isotope technique to quantify proximal and distal stomach emptying of a solid (100 g of 99mTc labelled liver/ground beef) liquid (either 200 ml of normal saline (eight subjects) or 25% dextrose (seven subjects) labelled with 113mIn-diethylenetriaminepenta-acetic acid) mixed meal. A manometric catheter simultaneously measured antral, pyloric, and duodenal motor activity. The liquid component dispersed rapidly throughout the stomach and emptied after a minimal lag period. The emptying of the 25% dextrose was delayed compared with the saline. This delay was associated with increased retention of the liquid in the distal stomach, a significant increase in localised phasic pyloric contractions, and a suppression of antral contractions. The solid component initially resided wholly within a proximal stomach reservoir area. Solids then redistributed from proximal to distal stomach during the emptying of liquid from the stomach. Dextrose delayed gastric emptying of solids compared with saline by increasing the solid lag period and retention in the proximal stomach. There was no significant difference between saline and dextrose meals in the distal stomach retention of solid or in the linear rate of emptying after the lag period. We conclude that, contrary to general opinion, the proximal stomach plays an important role in the control of gastric emptying of solids while the distal stomach is important in the emptying of nutrient liquids.     

Distinct neural ensemble response statistics are associated with recognition and discrimination of natural sound textures

The perception of sound textures, a class of natural sounds defined by statistical sound structure such as fire, wind, and rain, has been proposed to arise through the integration of time-averaged summary statistics. Where and how the auditory system might encode these summary statistics to create internal representations of these stationary sounds, however, is unknown. Here, using natural textures and synthetic variants with reduced statistics, we show that summary statistics modulate the correlations between frequency organized neuron ensembles in the awake rabbit inferior colliculus (IC). These neural ensemble correlation statistics capture high-order sound structure and allow for accurate neural decoding in a single trial recognition task with evidence accumulation times approaching 1 s. In contrast, the average activity across the neural ensemble (neural spectrum) provides a fast (tens of milliseconds) and salient signal that contributes primarily to texture discrimination. Intriguingly, perceptual studies in human listeners reveal analogous trends: the sound spectrum is integrated quickly and serves as a salient discrimination cue while high-order sound statistics are integrated slowly and contribute substantially more toward recognition. The findings suggest statistical sound cues such as the sound spectrum and correlation structure are represented by distinct response statistics in auditory midbrain ensembles, and that these neural response statistics may have dissociable roles and time scales for the recognition and discrimination of natural sounds.

What makes a sound natural, and what are the neural codes that support recognition and discrimination of real-world natural sounds? Although it is known that the early auditory system decomposes sounds along fundamental acoustic dimensions such as intensity and frequency, the higher-level neural computations that mediate natural sound recognition are poorly understood. This general lack of understanding is in part attributed to the structural complexity of natural sounds, which is difficult to study with traditional auditory test stimuli, such as tones, noise, or modulated sequences. Such stimuli can reveal details of the neural representation for relatively low-level acoustic cues, yet they don’t capture the rich and diverse statistical structure of natural sounds. Thus, they cannot reveal many of the computations associated with higher-level sound properties that facilitate auditory tasks such as natural sound recognition or discrimination. A class of stationary natural sounds termed textures, such as the random sounds emanating from a running stream, a crowded restaurant, or a chorus of birds, have been proposed as alternative natural stimuli which allow for manipulating high-level acoustic structure (1). Texture sounds are composed of spatially and temporally distributed acoustic elements that are collectively perceived as a single source and are defined by their statistical features. Identification of these natural sounds has been proposed to be mediated through the integration of time-averaged summary statistics, which account for high-level structures such as the sparsity and time-frequency correlation structure found in many natural sounds (1–3). Using a generative model of the auditory system to measure summary statistics from natural texture sounds, it is possible to synthesize highly realistic synthetic auditory textures (1). This suggests that high-order statistical cues are perceptually salient and that the brain might extract these statistical features to build internal representations of sounds.Although neural activity throughout the auditory pathway is sensitive to a variety of statistical cues such as the sound contrast, modulation power spectrum, and correlation structure (4–12), how sound summary statistics contribute toward basic auditory tasks such as recognition and discrimination of sounds is poorly understood. Furthermore, it is unclear where along the auditory pathway summary statistics are represented and how they are reflected in neural activity. The inferior colliculus (IC) is one candidate midlevel structure for representing such summary statistics. As the principal midbrain auditory nucleus, the IC receives highly convergent brainstem inputs with varied sound selectivities. Neurons in the IC are selective over most of the perceptually relevant range of sound modulations and neural activity is strongly driven by multiple high-order sound statistics (4–7, 10). In previous work, we showed the correlation statistics of natural sounds are highly informative about stimulus identity and they appear to be represented in the correlation statistics of auditory midbrain neuron ensembles (4). Correlations between neurons have also been proposed as mechanisms for pitch identification (13) and sound localization (14). This broadly supports the hypotheses that high-order sound statistics are reflected in the response statistics of neural ensembles and that these neural response statistics could potentially subserve basic auditory tasks.Here using natural and synthetic texture sounds, we test the hypothesis that statistical structure in natural texture sounds modulates the response statistics of neural ensembles in the IC of unanesthetized rabbits, and that distinct neural response statistics have the potential to contribute toward sound recognition and discrimination behaviors. By comparing the performance of neural decoders with human texture perception, we find that place rate representation of sounds (neural spectrum) accumulates evidence about the sounds on relatively fast time scales (tens of milliseconds) exhibiting decoding trends that mirror those seen for human texture discrimination. High-order statistical sound cues, by comparison, are reflected in the correlation statistics of neural ensembles, which require substantially longer evidence accumulation times (>500 ms) and follow trends that mirror those measured for human texture recognition. Collectively, the findings suggest that spectrum cues and accompanying place rate representation (neural spectrum) may contribute surprisingly little toward the recognition of auditory textures. Instead, high-order statistical sound structure is reflected in the distributed patterns of correlated activity across IC neural ensembles and such neural response structure has the potential to contribute toward the recognition of natural auditory textures.     

Relevance of Undetectably Rare Resistant Malaria Parasites in Treatment Failure: Experimental Evidence from Plasmodium chabaudi

Resistant malaria parasites are frequently found in mixed infections with drug-sensitive parasites. Particularly early in the evolutionary process, the frequency of these resistant mutants can be extremely low and below the level of molecular detection. We tested whether the rarity of resistance in infections impacted the health outcomes of treatment failure and the potential for onward transmission of resistance. Mixed infections of different ratios of resistant and susceptible Plasmodium chabaudi parasites were inoculated in laboratory mice and dynamics tracked during the course of infection using highly sensitive genotype-specific quantitative polymerase chain reaction (qPCR). Frequencies of resistant parasites ranged from 10% to 0.003% at the onset of treatment. We found that the rarer the resistant parasites were, the lower the likelihood of their onward transmission, but the worse the treatment failure was in terms of parasite numbers and disease severity. Strikingly, drug resistant parasites had the biggest impact on health outcomes when they were too rare to be detected by any molecular methods currently available for field samples. Indeed, in the field, these treatment failures would not even have been attributed to resistance.     

The major histocompatibility complex region marked by HSP70-1 and HSP70- 2 variants is associated with clozapine-induced agranulocytosis in two different ethnic groups

Genes of the major histocompatibility complex (MHC) have been associated with susceptibility to drug-induced adverse reactions. We previously found that clozapine-induced agranulocytosis (CA) is associated with the HLA-DRB1*0402, DRB4*0101, DQB1*0302, DQA1*0301 haplotype in Ashkenazi Jewish patients and with the HLA-DRB1*1601, DRB5*02, DQB1*0502, DQA1*0102 haplotype in non-Jewish patients. In the present study, we tested the hypothesis that the variants of the heat- shock protein 70 (HSP-70) encoded by the HSP-70 loci located within the MHC region and known to be involved in apoptosis and regulation of cell proliferation could play an important role in molecular mechanisms of CA. First, we analyzed HSP70-2 polymorphism in risk-associated haplotypes from HLA homozygous cells and normal individuals and confirmed that the HSP70-2 9-kb variant was associated invariably with DR4 (HLA-DRB1*0402, DQB1*0302) and DR2 (HLA-DRB1*01601, DQB1*0502, DQA1*0102 and HLA-DRB1*1501, DQB1*0602) haplotypes, which were the haplotypes found increased in Jewish and non-Jewish patients with CA, respectively. The 9.0-kb variant was also found to be associated with HLA-B44, DRB1*0401 and HLA-B44, DRB1*07 haplotypes. Second, in patients with CA (12 Ashkenazi Jewish and 20 non-Jewish patients), HSP70-1 A and HSP70-2 9.0-kb variants were associated with the MHC haplotypes found by us to be markers of susceptibility to CA. The clozapine-treated control group had an excess number of HSP70-1 C and HSP70-2 8.5-kb variants, consistent with genetic resistance to CA associated with those variants. This finding supports our hypothesis that a dominant gene within the MHC region (marked by HSP70-1 and HSP70-2), but not necessarily HLA, is associated with CA in two different ethnic groups.     

Insulin sensitivity and beta-cell function in protease inhibitor-treated and -naive human immunodeficiency virus-infected children

Previous pediatric studies have failed to demonstrate a clear association between protease inhibitor (PI) therapy and abnormal glucose homeostasis in HIV-infected children. To define more precisely the impact of PI therapy on glucose homeostasis in this population, we performed the insulin-modified frequent-sampling iv glucose tolerance test on 33 PI-treated and 15 PI-naive HIV-infected children. Other investigations included fasting serum lipids; glucose, insulin, and C-peptide; single-slice abdominal computed tomography; and, in a subset of PI-treated children, an oral glucose tolerance test.There were no differences between the two groups with respect to fasting serum insulin or C-peptide, homeostatic model assessment insulin resistance, or quantitative insulin sensitivity check index. The mean insulin sensitivity index of PI-treated and PI-naive children was 6.93 +/- 6.37 and 10.58 +/- 12.93 x 10(-4)min(-1) [microU/ml](-1), respectively (P = 0.17). The mean disposition index for the two groups was 1840 +/- 1575 and 3708 +/- 3005 x 10(-4)min(-1) (P = 0.013), respectively. After adjusting for potential confounding variables using multiple regression analysis, the insulin sensitivity index and disposition index of PI-treated children were significantly lower than that of PI-naive children (P = 0.01 for both). In PI-treated but not PI-naive children, insulin sensitivity correlated inversely with visceral adipose tissue area (r = -0.43, P = 0.01) and visceral to sc adipose tissue ratio (r = -0.49, P = 0.004). Mildly impaired glucose tolerance was noted in four of 21 PI-treated subjects tested.Our results demonstrate not only that PI therapy reduces insulin sensitivity in HIV-infected children but also that it impairs the beta-cell response to this reduction in insulin sensitivity and, in a subset of children, leads to the development of impaired glucose tolerance. The presence of insulin resistance, dyslipidemia, and the significant correlation of reduced insulin sensitivity with increased visceral adipose tissue content suggest that PI-containing highly active antiretroviral therapy is associated with the emergence of early features of a metabolic syndrome-like phenotype.     

Outcomes and risks of granulocyte colony-stimulating factor in patients with coronary artery disease.

OBJECTIVES: Cytokine mobilization of progenitor cells from bone marrow may promote myocardial neovascularization with relief of ischemia. BACKGROUND: Patients with coronary artery disease (CAD) have low numbers of endothelial progenitor cells compared with healthy subjects. METHODS: Granulocyte colony-stimulating factor (G-CSF), 10 microg/kg/day for five days, was administered to 16 CAD patients. Progenitor cells were measured by flow cytometry; ischemia was assessed by exercise stress testing and by dobutamine stress cardiac magnetic resonance imaging. RESULTS: Granulocyte colony-stimulating factor increased CD34+/CD133+ cells in the circulation from 1.5 +/- 0.2 microl to 52.4 +/- 10.4 microl (p < 0.001), similar to the response observed in 15 healthy subjects (75.1 +/- 12.6 microl, p = 0.173). Indices of platelet and coagulation activation were not changed by treatment, but C-reactive protein increased from 4.5 +/- 1.3 mg/l to 8.6 +/- 1.3 mg/l (p = 0.017). Two patients experienced serious adverse events: 1) non-ST-segment elevation myocardial infarction (MI) 8 h after the fifth G-CSF dose, and 2) MI and death 17 days after treatment. At 1 month after treatment, there was no improvement from baseline values (i.e., reduction) in wall motion score (from 25.7 +/- 2.1 to 28.3 +/- 1.9, p = 0.196) or segments with abnormal perfusion (7.6 +/- 1.1 to 7.7 +/- 1.1, p = 0.916) and a trend towards a greater number of ischemic segments (from 4.5 +/- 0.6 to 6.1 +/- 1.0, p = 0.068). There was no improvement in exercise duration at 1 month (p = 0.37) or at 3 months (p = 0.98) versus baseline. CONCLUSIONS: Granulocyte colony-stimulating factor administration to CAD patients mobilizes cells with endothelial progenitor potential from bone marrow, but without objective evidence of cardiac benefit and with the potential for adverse outcomes in some patients.     

Botrocetin (venom coagglutinin): reaction with a broad spectrum of multimeric forms of factor VIII macromolecular complex.

Botrocetin, originally called venom coagglutinin, is a Bothrops factor that causes aggregation of blood platelets in the presence of the von Willebrand component of the factor VIII macromolecular complex. The complex consists of a series of multimers with a molecular weight of about 1-20 x 10(6). Ristocetin, another agent that causes platelet aggregation dependent on von Willebrand factor, reacts with only the higher molecular weight multimers. We report on the reactivity of botrocetin in relation to the multimeric structure of the factor VIII complex. Several plasmas or plasma fractions with abnormal distribution of the multimeric sizes were examined, including variant von Willebrand disease type IIA with lack of the higher molecular weight forms, commercial antihemophilic factor concentrates with a preponderance of lower molecular weight forms, cryoprecipitate-free plasma containing mainly the smaller multimers, and a chromatographic fraction of plasma containing only the highest molecular weight polymers. Factor VIII-related antigen content was adjusted to 25-100%. All of the preparations lacking the high molecular weight forms caused prompt platelet aggregation with botrocetin, but none of them caused aggregation in the ristocetin test made isochronal with the botrocetin test. The very high molecular weight polymers were equally effective with botrocetin and ristocetin. These findings indicate that the Bothrops factor is reactive with a broad spectrum of high to low molecular weight forms of the factor VIII complex, suggesting that bioassays of von Willebrand factor with botrocetin should correlate better with immunoassays for factor VIII-related antigen and could reflect better the full platelet-aggregating function of the complex than do ristocetin determinations.