On the effect of biochemotherapy in metastatic malignant melanoma: an immunopathological evaluation

Although immunotherapy and biochemotherapy have shown promise, producing a subset of durable responses, for the majority of patients with metastatic melanoma the prognosis is still poor. Therefore there is a great need for predictive tests to identify patients with a high probability of responding. Furthermore, there is also a need for a better understanding of the mechanisms of action during treatment in order to be able to monitor the relevant antitumour reactivity during treatment and to optimize the efficacy of future immunotherapy and biochemotherapy. In the present study histopathological regression criteria were used to study the efficacy of biochemotherapy. Thirty-two patients with metastatic malignant melanoma (18 with regional disease and 14 with systemic disease) were treated with biochemotherapy (cisplatin 30 mg/m2 intravenously on days 1-3, dacarbazine 250 mg/m2 intravenously on days 1-3 and interferon-alpha2b 10 million IU subcutaneously 3 days a week, every 28 days). Pre-treatment fine needle aspirates were obtained from metastases to analyse the number of tumour-infiltrating CD4+ lymphocytes. Therapeutic efficacy was evaluated in metastases resected after treatment using histopathological criteria of tumour regression. Comparisons were also made with metastases from 17 untreated patients, all with regional disease. Regressive changes of 25% or more (of the section area) were found in two of the 17 untreated patients with regional disease compared with 13 of the 18 patients with regional disease and 10 of the 14 patients with systemic disease after biochemotherapy. Fifty per cent of the patients with regional disease showed a high degree of regressive changes (75-100% of the section area) after biochemotherapy. These results demonstrate the occurrence of an antitumour reactivity in the majority of patients. Patients with extensive regressive changes in 75-100% of the analysed biopsies were also found to have a longer overall survival (P = 0.019). In patients with regional disease there was a close correlation between a larger number of CD4+ lymphocytes pre-treatment and a higher degree of regressive changes post-treatment (P < 0.05). Thus, immunohistochemical analysis of tumour biopsies shortly after treatment seems to be a good surrogate endpoint. This technique also allows detailed analysis of antitumour reactivity and escape mechanisms.     

Image-guided spine surgery: state of the art and future directions

Navigation technology is a widely available tool in spine surgery and has become a part of clinical routine in many centers. The issue of where and when navigation technology should be used is still an issue of debate. It is the aim of this study to give an overview on the current knowledge concerning the technical capabilities of image-guided approaches and to discuss possible future directions of research and implementation of this technique. Based on a Medline search total of 1,462 publications published until October 2008 were retrieved. The abstracts were scanned manually for relevance to the topics of navigated spine surgery in the cervical spine, the thoracic spine, the lumbar spine, as well as ventral spine surgery, radiation exposure, tumor surgery and cost-effectivity in navigated spine surgery. Papers not contributing to these subjects were deleted resulting in 276 papers that were included in the analysis. Image-guided approaches have been investigated and partially implemented into clinical routine in virtually any field of spine surgery. However, the data available is mostly limited to small clinical series, case reports or retrospective studies. Only two RCTs and one metaanalysis have been retrieved. Concerning the most popular application of image-guided approaches, pedicle screw insertion, the evidence of clinical benefit in the most critical areas, e.g. the thoracic spine, is still lacking. In many other areas of spine surgery, e.g. ventral spine surgery or tumor surgery, image-guided approaches are still in an experimental stage. The technical development of image-guided techniques has reached a high level as the accuracies that can be achieved technically meet the anatomical demands. However, there is evidence that the interaction between the surgeon (‘human factor’) and the navigation system is a source of inaccuracy. It is concluded that more effort needs to be spend to understand this interaction.     

The Prognostic Value of Prothrombin Time in Predicting Survival after Major Trauma: a Prospective Analysis of 1,351 Patients from the German Trauma Registry

Background: Early assessment of the individual trauma load in major trauma patients is difficult. A simple and reliable prognostic factor already available in the emergency room would help the emergency physician to make appropriate therapeutic decisions, e. g., when and how to operate on major fractures. The aim of the study was to evaluate the prognostic value of prothrombin time (PT). Patients and Methods: The German Trauma Registry is a prospective, standardized and anonymous documentation of severely injured patients. 3,814 patients were included in the registry. 1,351 patients with an Injury Severity Score (ISS) h 16 and complete data for specific variables (PT, Trauma Score + Injury Severity Score [TRISS], survival until discharge) were included in the study. The PT was measured on the patient's arrival in the emergeny room. Three different analyses were performed. 1. According to clinical judgment, three groups of patients were compared (PT S 60%, PT 40-59%, PT < 40%). A univariate analysis compared therapeutic interventions and outcome variables between the three groups. 2. A receiver-operator-characteristic (ROC) curve analysis compared the performance of PT with the prognostic standard TRISS. 3. A multivariate logistic regression was performed in order to evaluate PT as an independent prognostic variable. Results: PT values showed a good inverse correlation with the severity of injury and the level of therapeutic interventions. The ROC analysis as well as the regression revealed PT as a significant prognostic factor although it showed a slightly worse performance compared to TRISS. Conclusions: As PT, in contrast to TRISS, is readily available already in the emergency room, it can be used as a screening variable for the assessment of a patient's trauma load and thereby help in the decision-making for further operative treatment of major trauma patients.     

Microwaves from GSM mobile telephones affect 53BP1 and gamma-H2AX foci in human lymphocytes from hypersensitive and healthy persons

The data on biologic effects of nonthermal microwaves (MWs) from mobile telephones are diverse, and these effects are presently ignored by safety standards of the International Commission for Non-Ionizing Radiation Protection (ICNIRP). In the present study, we investigated effects of MWs of Global System for Mobile Communication (GSM) at different carrier frequencies on human lymphocytes from healthy persons and from persons reporting hypersensitivity to electromagnetic fields (EMFs). We measured the changes in chromatin conformation, which are indicative of stress response and genotoxic effects, by the method of anomalous viscosity time dependence, and we analyzed tumor suppressor p53-binding protein 1 (53BP1) and phosphorylated histone H2AX (gamma-H2AX), which have been shown to colocalize in distinct foci with DNA double-strand breaks (DSBs), using immunofluorescence confocal laser microscopy. We found that MWs from GSM mobile telephones affect chromatin conformation and 53BP1/gamma-H2AX foci similar to heat shock. For the first time, we report here that effects of MWs from mobile telephones on human lymphocytes are dependent on carrier frequency. On average, the same response was observed in lymphocytes from hypersensitive and healthy subjects.     

Adenosine A1 receptors are crucial in keeping an epileptic focus localized

Adenosine is an endogenous neuromodulator with anticonvulsant and neuroprotective properties presumably mediated by activation of adenosine A1 receptors (A1Rs). To study the involvement of A1Rs in neuroprotection during epileptogenesis, we induced status epilepticus by a unilateral intrahippocampal kainic acid (KA) injection (1 nmol) in wild-type C57BL/6 and homozygous adenosine A1R knock out (A1R-KO) mice of the same genetic background. Whereas the KA injection caused non-convulsive status epilepticus in wild-type mice, in A1R-KO mice KA induced status epilepticus with severe convulsions and subsequent death of the animals within 5 days. 24 h after KA injection, brains from wild-type C57BL/6 mice were characterized by slight neuronal cell loss confined to the immediate location of the KA injection. In contrast, KA-injected A1R-KO mice displayed massive neuronal cell loss in the ipsilateral hippocampus, and, importantly, the contralateral hippocampus was also affected with significant cell loss in the hilus and in the CA1 region of the pyramidal cell layer. We conclude that activation of A1 receptors by ambient adenosine is crucial in keeping epileptic foci localized. These results open up a new dimension of the A1 receptor's role in controlling excitotoxic cell death and further demonstrate its importance in preventing the progression of status epilepticus to lethal consequences.     

Urban background particulate matter and allergic sensitization in adults of ECRHS II

BACKGROUND: Epidemiological studies have shown weak or inconsistent associations between ambient air pollutants and allergic sensitization. The aim of this study was to evaluate whether regional urban air pollution may partly explain the large variation in the prevalence of allergic sensitization across cities of the European Community Respiratory Health Survey (ECRHS) II. METHODS: ECRHS is a cross-sectional survey initiated in 29 countries across Europe in the 1990s (ECRHS I) with a follow-up conducted 10 years later (ECRHS II). Subject characteristics were measured by questionnaires and blood tests conducted for the measurement of specific immunoglobulin E. Fine particle mass (PM(2.5), <2.5 microm) and sulphur on PM(2.5) were measured in 21 centres and annual averages of urban regional background air pollution were calculated. Results were scaled by an interquartile range increase in ambient PM(2.5) (6.03 microg/m(3)) and sulphur (1336 ng/m(3)). Generalized estimating equations were applied to compute population average effect estimates with adjustment for age, gender, smoking habit, education and number of siblings. RESULTS: A notable variation in pollution level and prevalence of allergic sensitization was observed. Moreover, exposure to urban regional background air pollution was not associated with allergic sensitization; adjusted odds ratios and 95% confidence interval were 1.02 (0.95-1.09) for PM(2.5) and 1.08 (0.86-1.31) for sulphur. These statistically non-significant associations were sensitive to model specification. CONCLUSIONS: The study suggests that regional air pollution measured at fixed sites is not associated with allergic sensitization among adults in ECRHS II.     

The effect of temperature on mortality in Stockholm 1998--2003: a study of lag structures and heatwave effects

AIMS: To describe seasonal patterns of natural mortality in Stockholm as well as the temperature-mortality relationship and the lag structure for effects of high and low temperatures; to describe the impact of high temperatures on cardiovascular and respiratory mortality, and the general effect of high temperatures in different age groups; and to investigate whether there is any indication of an additional heatwave or cold spell effect. METHODS: Generalized additive Poisson regression models were fitted to mortality and temperature data from Stockholm from the period 1998-2003, controlling for influenza, season, time trends, week day, and holidays. RESULTS: The mortality in Stockholm followed a seasonal pattern, with a peak in the winter season. The ;;optimal temperature' was around 11-12 degrees C. Above this temperature, the cumulative general relative risk (RR) corresponded to a 1.4% (95% confidence interval (CI)=0.8-2.0) increase per degrees C, and below this temperature the cumulative RR corresponded to a 0.7% (95% CI=0.5-0.9) decrease per degrees C. Age-specific RRS were estimated above the threshold for age <65 years, age 65-74 years, and age >74 years, with estimated increases of 0.5% (not significant), 1.5% (not significant) and 1.6% (95% CI=0.9-2.3) per degrees C, respectively. The RRs for cardiovascular and respiratory causes were studied above the breakpoint, and estimated to be 1.1% (95% CI=0.3-2.0) and 4.3% (95% CI=2.2-6.5) per degrees C, respectively. The lag structures from moving averages and polynomial distributed lag models coincided with a rather direct effect during summer (lag 0 and 1) and a more prolonged effect during winter, covering about a week. The inclusion of an indicator of heatwaves added an increase in daily mortality of 3.1-7.7%, depending on the threshold. CONCLUSIONS: These results show that the predicted increase in heat events must also be taken seriously in Scandinavia, whatever the extent of the decreasing cold related mortality. The relative risks associated with heat and heatwaves seem stronger than the cold effects and thus a larger public health threat, since northern populations have not yet adapted to heat as have been done over a long time for the cold periods. The pressure on the healthcare sector will probably increase in the warm season, periodically it may become even greater than the pressure due to cold weather, which will be a new phenomenon for the healthcare sector to cope with. We need to be prepared for these kind of events by developing adaptation and education strategies to handle the consequences that a warmer climate will have for public health and the healthcare sector.     

Arthroscopy vs. MRI for a detailed assessment of cartilage disease in osteoarthritis: diagnostic value of MRI in clinical practice

Background  

In patients with osteoarthritis, a detailed assessment of degenerative cartilage disease is important to recommend adequate treatment. Using a representative sample of patients, this study investigated whether MRI is reliable for a detailed cartilage assessment in patients with osteoarthritis of the knee.     

Über die Topographie des Conus medullaris bei Säuglingen; ein Beitrag zur Methodik der Lumbalpunktion bei Säuglingen

Ohne ZusammenfassungMit 7 Textabbildungen.