Neuronal activity in the monkey striatum during conditional visuomotor learning

The brainstem projection of the saccular nerve was investigated by transganglionic tracing with horseradish peroxidase in the cat. The labeled fibers were located most caudally and laterally (dorsolaterally) in the vestibular nerve root. This was unique when compared with the locations of the fibers from the nerves of the other vestibular-end organs that were studied by the present authors by the same approach previously. In addition, such a comparison revealed a specific location, from lateral to medial, for the fibers from each of the five divisions of the vestibular nerve. In the present study, labeled fibers from the sacculus, of fine caliber, were found close to the restiform body, both medially and laterally, some even penetrating through this structure. Labeled terminals were present in cell group "y". This was unique, compared with the nerves from the other end organs. Such terminals were also found in the four main vestibular nuclei, except for the medial vestibular nucleus, where no labeled terminals could be detected. No labeled terminals were found in the interstitial nucleus of the vestibular nerve. Together with the findings from our previous studies, this suggests that, in contrast to the ampullar nerves, the nerves from the maculae do not project to this structure. This study confirms, but also extends, findings reported from a previous investigation in the cat, using an experimental degeneration technique. This article is based on experimental material that was prepared before the untimely death of Dr. Siegborn in 1997. He took active part in the planning of this study, and he carried out all of the microsurgery     

Shiga toxin 2 and lipopolysaccharide induce human microvascular endothelial cells to release chemokines and factors that stimulate platelet function

Shiga toxins (Stxs) produced by Shigella dysenteriae type 1 and enterohemorrhagic Escherichia coli are the most common cause of hemolytic-uremic syndrome (HUS). It is well established that vascular endothelial cells, mainly those located in the renal microvasculature, are targets for Stxs. The aim of the present research was to evaluate whether E. coli-derived Shiga toxin 2 (Stx2) incubated with human microvascular endothelial cells (HMEC-1) induces release of chemokines and other factors that might stimulate platelet function. HMEC-1 were exposed for 24 h in vitro to Stx2, lipopolysaccharide (LPS), or the Stx2-LPS combination, and chemokine production was assessed by immunoassay. More interleukin-8 was released than stromal cell-derived factor 1alpha (SDF-1alpha) or SDF-1beta and RANTES. The Stx2-LPS combination potentiated chemokine release, but Stx2 alone caused more release of SDF-1alpha at 24 h than LPS or Stx2-LPS did. In the presence of low ADP levels, HMEC-1 supernatants activated platelet function assessed by classical aggregometry, single-particle counting, granule secretion, P-selectin exposure, and the formation of platelet-monocyte aggregates. Supernatants from HMEC-1 exposed only to Stx2 exhibited enhanced exposure of platelet P-selectin and platelet-THP-1 cell interactions. Blockade of platelet cyclooxygenase by indomethacin prevented functional activation. The chemokine RANTES enhanced platelet aggregation induced by SDF-1alpha, macrophage-derived chemokine, or thymus and activation-regulated chemokine in the presence of very low ADP levels. These data support the hypothesis that microvascular endothelial cells exposed to E. coli O157:H7-derived Stx2 and LPS release chemokines and other factors, which when combined with low levels of primary agonists, such as ADP, cause platelet activation and promote the renal thrombosis associated with HUS.     

The consequences of insulin-like growth factors/receptors dysfunction in lung cancer

The aim of this study was to investigate the consequences of insulin-like growth factors (IGF) and IGF receptor dysfunction in lung carcinomas. A correlation between increased expression (at mRNA and protein levels) for IGF-1 and IGF-1R and decreased apoptosis were found in large-cell carcinomas and adenocarcinomas. In 40% of informative adenocarcinomas expressing the highest values of IGF-2 and Ki-67 proteins, M6P/IGF-2R gene had LOH at one allele and a mutation in another allele. All four squamous cell carcinoma samples expressed LOH/mutation in the M6P/IGF-2R gene. The alphaIR3 strongly diminished proliferation and increased apoptosis in cultures established from squamous cell carcinomas overexpressing IGF-2 and IGF-1R. Telomerase activity was assessed in four squamous cell carcinomas. Cell treatment with IGF-1 increased telomerase activity. The opposite was observed when the cells were treated with alphaIR3, which inhibits the activity of IGF-1 receptors. Our findings suggest that disruption of the IGF/IGF receptors axis is involved in lung cancer formation.     

Evaluation of new treatments in radiation oncology: are they better than standard treatments?

Context  The superiority of innovative over standard treatments is not known. To describe accurately the outcomes of innovations that are tested in randomized controlled trials (RCTs) 3 factors have to be considered: publication rate, quality of trials, and the choice of the adequate comparator intervention. Objective  To determine the success rate of innovative treatments by assessing preferences between experimental and standard treatments according to original investigators’ conclusions, determining the proportion of RCTs that achieved primary outcomes’ statistical significance, and performing meta-analysis to examine if the summary point estimate favored innovative vs standard treatments. Data Sources  Randomized controlled trials conducted by the Radiation Therapy Oncology Group (RTOG). Study Selection  All completed phase 3 trials conducted by the RTOG since its creation in 1968 until 2002. For multiple publications of the same study, we used the one with the most complete primary outcomes and with the longest follow-up information. Data Extraction  We used the US National Cancer Institute definition of completed studies to determine the publication rate. We extracted data related to publication status, methodological quality, and treatment comparisons. One investigator extracted the data from all studies and 2 independent investigators extracted randomly about 50% of the data. Disagreements were resolved by consensus during a meeting. Data Synthesis  Data on 12 734 patients from 57 trials were evaluated. The publication rate was 95%. The quality of trials was high. We found no evidence of inappropriateness of the choice of comparator. Although the investigators judged that standard treatments were preferred in 71% of the comparisons, when data were meta-analyzed innovations were as likely as standard treatments to be successful (odds ratio for survival, 1.01; 99% confidence interval, 0.96-1.07; P = .5). In contrast, treatment-related mortality was worse with innovations (odds ratio, 1.76; 99% confidence interval, 1.01-3.07; P = .008). We found no predictable pattern of treatment successes in oncology: sometimes innovative treatments are better than the standard ones and vice versa; in most cases there were no substantive differences between experimental and conventional treatments. Conclusion  The finding that the results in individual trials cannot be predicted in advance indicates that the system and rationale for RCTs is well preserved and that successful interventions can only be identified after an RCT is completed.      

Standards,Options and Recommendations 2000: non metastatic endometrial cancer

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of French Cancer Centers (FNCLCC), the 20 French Cancer Centers, and specialists from French Public Universities, General Hospitals and Private Clinics, and some specialists learned societies. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients. The SORs are developed using a methodology based on a literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. Objectives: To develop clinical practice guidelines for the management of patients with carcinoma of the endometrium according to the definitions of the Standards, Options and Recommendations project. METHODS: Data were identified by searching Medline , web sites, and using the personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to 63 independent reviewers. RESULTS: The main recommendations for the management of carcinoma of the endometrium are: 1) The diagnosis of carcinoma of the endometrium is based on biopsy and histological examination. However, as first intention, the first elements for diagnosis can be obtain from a hysterography, or particularly, a endovaginal ultrasound examination. Ultrasound allows locoregional metastases to be detected, the CT scan allows the lymph node involvement to be assessed and magnetic resonance imaging allows the myometrium invasion to be evaluated. 2) For the majority of patients, surgery is the initial treatment, both for localised and advanced-stage carcinomas. The excised sample can be used for pathological analysis and tumour staging, using the FIGO (Fédération internationale de gynécologie obstétrique) classification. Surgery for patients with stage I and II carcinomas involves total extrafascial hysterectomy with bilateral salpingo-oophorectomy., In patients with stage III and IV carcinomas radical surgery should be performed, when possible. If this is not possible, then surgery should be as complete as possible and be associated with a complementary treatment. In patients with the most advanced carcinomas, tumour reduction by surgery should be performed. 3) Complementary treatment includes external-beam radiotherapy and brachytherapy. The decision concerning the extent and type of irradiation should be taken taking into consideration the stage and the prognostic factors present. For patients with stage I and II carcinoma, complementary treatment with brachytherapy can be performed, if the myometrium invasion is not deep, or if the carcinoma is grade 2 or 3. Patients with stage III carcinomas can be treated with pelvic or abdominal-pelvic complementary irradiation. In patients that cannot undergo surgery, exclusive radiotherapy can be performed. 4) In the absence of any symptoms, surveillance should include a general clinical and gynaecological examination. All patients with symptoms should undergo an additional work-up.     

Adult onset Still's disease

Summary Three patients with adult onset of Still's disease are presented. Common early findings were: septic fever, polyarthralgia, leukocytosis, neutrophilia and elevated sedimentation rate. All of them had abnormal liver function tests which returned to normal values following corticosteroid therapy. It is proposed that hepatic abnormalities in adult onset of Still's disease reflect the basic disease process.     

The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans

Nonalcoholic fatty liver disease (NAFLD) is associated with all features of the metabolic syndrome. Although deposition of excess triglycerides within liver cells, a hallmark of NAFLD, is associated with a loss of insulin sensitivity, it is not clear which cellular abnormality arises first. We have explored this in mice overexpressing carbohydrate responsive element-binding protein (ChREBP). On a standard diet, mice overexpressing ChREBP remained insulin sensitive, despite increased expression of genes involved in lipogenesis/fatty acid esterification and resultant hepatic steatosis (simple fatty liver). Lipidomic analysis revealed that the steatosis was associated with increased accumulation of monounsaturated fatty acids (MUFAs). In primary cultures of mouse hepatocytes, ChREBP overexpression induced expression of stearoyl-CoA desaturase 1 (Scd1), the enzyme responsible for the conversion of saturated fatty acids (SFAs) into MUFAs. SFA impairment of insulin-responsive Akt phosphorylation was therefore rescued by the elevation of Scd1 levels upon ChREBP overexpression, whereas pharmacological or shRNA-mediated reduction of Scd1 activity decreased the beneficial effect of ChREBP on Akt phosphorylation. Importantly, ChREBP-overexpressing mice fed a high-fat diet showed normal insulin levels and improved insulin signaling and glucose tolerance compared with controls, despite having greater hepatic steatosis. Finally, ChREBP expression in liver biopsies from patients with nonalcoholic steatohepatitis was increased when steatosis was greater than 50% and decreased in the presence of severe insulin resistance. Together, these results demonstrate that increased ChREBP can dissociate hepatic steatosis from insulin resistance, with beneficial effects on both glucose and lipid metabolism.