Osteosarcoma of the pelvis: experience of the Cooperative Osteosarcoma Study Group.

PURPOSE: To define patients and tumor characteristics as well as therapy results, patients with pelvic osteosarcoma who were registered in the Cooperative Osteosarcoma Study Group (COSS) were analyzed. PATIENTS AND METHODS: Sixty-seven patients with a high-grade pelvic osteosarcoma were eligible for this analysis. Fifteen patients had primary metastases. All patients received chemotherapy according to COSS protocols. Thirty-eight patients underwent limb-sparing surgery, 12 patients underwent hemipelvectomy, and 17 patients did not undergo definitive surgery. Eleven patients received irradiation to the primary tumor site: four postoperatively and seven as the only form of local therapy. RESULTS: Local failure occurred in 47 of all 67 patients (70%) and in 31 of 50 patients (62%) who underwent definitive surgery. Five-year overall survival (OS) and progression-free survival rates were 27% and 19%, respectively. Large tumor size (P =.0137), primary metastases (P =.0001), and no or intralesional surgery (P <.0001) were poor prognostic factors. In 30 patients with no or intralesional surgery, 11 patients with radiotherapy had better OS than 19 patients without radiotherapy (P =.0033). Among the variables, primary metastasis, large tumor, no or intralesional surgery, no radiotherapy, existence of primary metastasis (relative risk [RR] = 3.456; P =.0009), surgical margin (intralesional or no surgical excision; RR = 5.619; P <.0001), and no radiotherapy (RR = 4.196; P =.0059) were independent poor prognostic factors. CONCLUSION: An operative approach with wide or marginal margins improves local control and OS. If the surgical margin is intralesional or excision is impossible, additional radiotherapy has a positive influence on prognosis.     

Hair cell loss and regeneration after severe acoustic overstimulation in the adult pigeon

The extent of hair cell regeneration following acoustic overstimulation severe enough to destroy tall hair cells, was determined in adult pigeons. BrdU (5-bromo-2′-deoxyuridine) was used as a proliferation marker. Recovery of hearing thresholds in each individual animal was measured over a period of up to 16 weeks after trauma. In ears with loss of both short and tall hair cells, little or no functional recovery occurred. In ears with less damage, where significant functional recovery did occur, there were always a few rows of surviving hair cells left at the neural edge of the basilar papilla. In the region of hair cell loss, numerous BrdU labeled cells were found. However, only a small minority of these cells were regenerated hair cells, the majority being monolayer cells. Irrespective of the extent of the region of hair cell loss, regenerated hair cells were observed predominantly in a narrow strip at the transition from the abneural area of total hair cell loss and the neural area of hair cell survival. With increasing damage this strip moved progressively towards the neural edge of the papilla. No regeneration of hair cells was observed in the abneural region of total hair cell loss, even up to 16 weeks after trauma. The results indicate that there is a gradient in the destructive effect of loud sound across the width of the basilar papilla, from most detrimental at the abneural edge to least detrimental at the neural edge. Both tall and short hair cells can regenerate after sound trauma. Whether they do regenerate or not depends on the degree of damage to the area of the papilla where they normally reside. Regeneration of new hair cells occurs only in a narrow longitudinal band, which moves from abneural into the neural direction with increasing damage. In the area neural to this band, hair cells survive the overstimulation. In the area abneural to this band, sound damage is so severe, that no regeneration of hair cells occurs. As a consequence morphological and functional deficits persist.     

The effects of acamprosate and neramexane on cue-induced reinstatement of ethanol-seeking behavior in rat.

This study examines, for the first time, the effects of acamprosate and the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist neramexane on ethanol-seeking induced by alcohol-related environmental stimuli in an animal model of relapse. Wistar rats were trained to operantly self-administer ethanol (10% w/v) or water on a fixed-ratio 1 schedule in a 30-min daily session. Ethanol availability was signaled by an olfactory discriminative stimulus of orange extract (S+). In addition, each lever press was accompanied by a 5-s illumination of the operant chamber's house light (CS+). Water availability was signaled by anise odor (S-) and 5-s white noise stimulus (CS-). After completion of the conditioning phase, indicated by stable levels of responding, operant behaviors were extinguished. Prior to reinstatement tests, animals were divided into groups according to either treatment with acamprosate (100, 200 mg/kg given twice), neramexane (1.0, 2.0, 4.0 mg/kg), or vehicle. In vehicle-treated rats, re-exposure to the S+/CS+ in the absence of further ethanol availability elicited strong recovery of responding. No effect was observed following presentation of water-paired cues (S-/CS-). Acamprosate dose-dependently attenuated recovery of responding elicited by ethanol-paired cues (S+/CS+), whereas responding under S-/CS- was not modified by drug administration. Treatment with 1.0 and 2.0 mg/kg of neramexane did not significantly modify responding under both S+/CS+ and S-/CS- conditions. However, a slight reduction of cue-induced reinstatement of alcohol seeking was observed. At the dose of 4.0 mg/kg, neramexane elicited a marked inhibition of responding following presentation of both ethanol- and water-paired cues. In conclusion, acamprosate significantly and selectively reduced alcohol-seeking elicited by environmental stimuli predictive of alcohol availability. Treatment with neramexane that shares part of the pharmacological effects of acamprosate on NMDA receptors, however, resulted in a nonselective reduction of lever responding.     

Ergebnisse der Herzinfarktregister in Chemnitz 1974–1999

Myocardial infarction has great importance for the populations in industrial countries because of the high morbidity and mortality rates. For research of the epidemiological trends in the 1970s and especially in the 1980s, the World Health Organization (WHO) began registering myocardial infarction throughout the world. The most important aspect was the WHO Monitoring of Trends and Determinants of Cardiovascular Diseases (MONICA) project. From 1974 to 1994 and in 1999 in Chemnitz, Germany, data from patients with acute myocardial infarction were collected for the myocardial infarction register. Despite changes in the event rates from year to year, no decrease in the number of myocardial infarctions in the German population aged 25–64 years was detected, contrary to the trend in the Western industrial states in the period from 1984 to 1994. The event rates in men were significantly higher than in women. In 1999, a significant decrease in the event rates in men and women was found. This may be explained by an incomplete registration of patients with myocardial infarction in 1999 because of the change in the structure of the Public Health System. The highest 28-day fatality rates in men were detected in 1989 and 1990. In women with classic myocardial infarction, a decrease in the 28-day fatality rates after 1993 was recorded, reaching lower rates than those of men. Despite methodological problems, the myocardial infarction register can contribute to a comparison of the morbidity, mortality and case fatality rates of myocardial infarction for a longer period.     

Autonomic neuropathy in patients with HIV: Course, impact of disease stage, and medication

The purpose of this article is to examine the prevalence, degree, and natural course of pupillary neuropathy (PANP), cardiovascular autonomic neuropathy (CANP), and sensorimotor neuropathy (SNP) and to study the impact of disease stage and medication on neuropathy in 61 consecutive patients with HIV. PANP, CANP, and SNP were assessed by standardized test procedures. Overall prevalence of PANP, CANP, and SNP were 66%, 15%, and 15%, respectively. The maximal pupillary area (pupillary measure, p<0.0001) and the lying-to-standing ratio (cardiovascular measure, p<0.0001) were abnormal as compared with control subjects. The changes in CD4+ T-lymphocytes and respiratory sinus arrhythmia percentile during 2 years of follow-up correlated significantly (r=0.758, p=0.007). Patients with CANP were more often in an advanced disease stage than patients without CANP (p=0.004). SNP, but not PANP or CANP, was associated with the intake of the neuropathogenic drugs dideoxycytidine, dideoxyinosine, and 2,3 didehydro-2,3 dideoxythymidine (p<0.05). Autonomic and sensorimotor neuropathy are frequent in patients with HIV, and progression of CANP may put patients at risk for unexpected cardiorespiratory arrest.     

Calcium-binding proteins S100A8 and S100A9 as novel diagnostic markers in human prostate cancer.

PURPOSE: S100 proteins comprise a family of calcium-modulated proteins that have recently been associated with epithelial tumors. We examined the expression of two members of this family, S100A8 and S100A9, together with the S100 receptor RAGE (receptor for advanced glycation end products) in human prostate adenocarcinomas and in prostatic intraepithelial neoplasia. EXPERIMENTAL DESIGN: Tissue specimens of 75 patients with organ-confined prostate cancer of different grades were analyzed by immunohistochemistry for expression of S100A8, S100A9, and RAGE. In addition, in situ hybridization of S100A8 and S100A9 was done for 20 cases. An ELISA was applied to determine serum concentrations of S100A9 in cancer patients compared with healthy controls or to patients with benign prostatic hyperplasia (BPH). RESULTS: S100A8, S100A9, and RAGE were up-regulated in prostatic intraepithelial neoplasia and preferentially in high-grade adenocarcinomas, whereas benign tissue was negative or showed weak expression of the proteins. There was a high degree of overlap of S100A8 and S100A9 expression patterns and of S100A8 or S100A9 and RAGE, respectively. Frequently, a gradient within the tumor tissue with an increased expression toward the invaded stroma of the prostate was observed. S100A9 serum levels were significantly elevated in cancer patients compared with BPH patients or healthy individuals. CONCLUSION: Our data suggest that enhanced expression of S100A8, S100A9, and RAGE is an early event in prostate tumorigenesis and may contribute to development and progression or extension of prostate carcinomas. Furthermore, S100A9 in serum may serve as useful marker to discriminate between prostate cancer and BPH.     

Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS).

PURPOSE: To evaluate the impact of patient, tumor, and treatment-related factors on outcome in unselected patients with recurrent osteosarcoma. PATIENTS AND METHODS: Five hundred seventy-six consecutive patients who had achieved a first complete surgical remission (CR) during combined-modality therapy on neoadjuvant Cooperative Osteosarcoma Study Group (COSS) protocols and then developed recurrent osteosarcoma were analyzed (median time from biopsy to relapse, 1.6 years; range, 0.1 to 14.3 years). There were 501 patients with metastases, 44 with local recurrences, and 31 with both. Metastases involved lungs (469 patients), bones (90 patients), and/or other sites (54 patients). RESULTS: After a median follow-up of 1.2 years for all patients and 4.2 years for survivors, actuarial overall survival (OS) rates at 2, 5, and 10 years were 0.38, 0.23, and 0.18, respectively. Five-year OS was 0.39 for 339 patients with and 0.00 for 229 patients without a second surgical CR (P < .0001). A long time to relapse, a solitary lesion, and, in the case of pulmonary metastases, unilateral disease and the absence of pleural disruption, were of positive prognostic value in uni- and multivariate analyses, as were a second surgical CR and the use of second-line chemotherapy. Radiotherapy was associated with moderately prolonged survival in patients without a second CR. The very limited prognostic differences associated with the use of second-line chemotherapy appeared to be more pronounced with polychemotherapy. CONCLUSION: Time to relapse and tumor burden correlate with postrelapse outcome in osteosarcoma. Complete surgery is an essential component of curative second-line therapy. Chemotherapy, particularly chemotherapy with more than one agent, may contribute to limited improvements in outcome.     

BDNF serum concentrations in healthy volunteers are associated with depression-related personality traits.

The issue of neurotrophins is recognized as a new lead in the quest for a deeper understanding of mood disorders. This hypothesis has emerged from experimental evidence suggesting that antidepressant drugs might work by a neuroprotective effect through the stimulation of the neurotrophin expression in distinct regions of the CNS. Endogenous levels of BDNF protein were measured in the serum samples of 118 healthy unrelated volunteers (64 male, 54 female, age: 42.1+/-13.0 years), and the NEO-FFI has been performed in all subjects. BDNF serum values amounted to 16.3+/-7.3 ng/ml. BDNF concentration correlated significantly with age (r=0.182, p=0.048), but showed no gender differences (male 16.1+/-7.2, female 16.5+/-7.4 ng/ml). A negative correlation between the BDNF serum concentration and the depression-related factor neuroticism (r=-0.212, p=0.022) has been found. Low BDNF levels in healthy humans with depressive personality traits might constitute a risk marker, reflecting a personality profilethat is linked to vulnerability to mood disorders. These results provide further support for the hypothesis that BDNF may be central to the development of depressive mood states.     

mGluR5 antagonist MPEP reduces ethanol-seeking and relapse behavior.

The glutamatergic system plays an important role in mediating neurobehavioral effects of ethanol. Metabotropic glutamate receptors subtype 5 (mGluR5) are modulators of glutamatergic neurotransmission and are abundant in brain regions known to be involved in ethanol self-administration. Here, we studied the effects of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a highly potent, noncompetitive mGlu5 receptor antagonist, on voluntary ethanol consumption and relapse behavior. For this purpose, we used two models for the measurement of relapse behavior: (i) reinstatement of ethanol-seeking behavior by drug-associated cues and (ii) the alcohol deprivation effect in long-term ethanol-consuming rats. In the first set of experiments, rats were trained to lever press for ethanol in the presence of a distinct set of cues. After extinction, the animals were exposed to the respective cues that initiated reinstatement of responding. A response-contingent ethanol prime further enhanced responding compared to the conditioned cues alone. Under these conditions, MPEP (0, 1, 3, and 10 mg/kg) attenuated ethanol seeking significantly and in a dose-related manner. However, at the highest dose, MPEP also decreased the number of inactive lever responses. In the second set of experiments, rats with 1 year of ethanol experience and repeated deprivation phases were used. A subchronic treatment with MPEP (twice daily; 0, 3, and 10 mg/kg) resulted in a significant and dose-dependent reduction of the alcohol deprivation effect (ADE). Although the same MPEP treatment regimen decreased baseline drinking, this effect was not as pronounced as on the ADE. These results show in two commonly used models of relapse to ethanol that pharmacological targeting of mGlu5 receptors may be a promising approach for the treatment of alcoholism.     

Automated multicolor mesoscopic imaging for the 3-dimensional reconstruction of fluorescent biomarker distribution in large tissue specimens

Research in translational medicine often requires high-resolution characterization techniques to visualize or quantify the fluorescent probes. For example, drug delivery systems contain fluorescent molecules enabling in vitro and in vivo tracing to determine biodistribution or plasma disappearance. Albeit fluorescence imaging systems with sufficient resolution exist, the sample preparation is typically too complex to image a whole organism of the size of a mouse. This article established a mesoscopic imaging technique utilizing a commercially available cryo-microtome and an in-house built episcopic imaging add-on to perform imaging during serial sectioning. Here we demonstrate that our automated red, green, blue (RGB) and fluorescence mesoscope can generate sequential block-face and 3-dimensional anatomical images at variable thickness with high quality of 6 µm × 6 µm pixel size. In addition, this mesoscope features a numerical aperture of 0.10 and a field-of-view of up to 21.6 mm × 27 mm × 25 mm (width, height, depth).