Cytotoxic Effect of Brain Macrophages on Developing

Brain macrophages are transiently present in different regions of the central nervous system during development or in the course of tissue remodelling following various types of injuries. To investigate the influence of these phagocytes on neuronal growth and survival, brain macrophages stemming from the cerebral cortex of rat embryos were added to neuronal primary cultures. A neurotoxic effect of brain macrophages was demonstrated by the reduction of the number of neurons bearing neurites within two days of contact between the two cell types. Neuronal death and phagocytosis were also directly observed in video recordings of living cultures. This toxicity involved the production by brain macrophages of reactive oxygen intermediates, as shown by the protective effect of catalase, a scavenger of H2O2. In addition, the respiratory bursts of brain macrophages were stimulated in the presence of neurons. These results suggest that brain macrophages could favour the appearance of neuroregressive events which occur either during neurogenesis or in neurodegenerative diseases, implying intracerebral recruitment of mononuclear phagocytes.     

Catalysis of nitrosation in vitro and in vivo in rats by catechin and resorcinol and inhibition by chlorogenic acid

Measurements were made of the effects of phenolic compounds,some of which are present in the human diet, on the nitrosationof proline by nitrite to give N-nitrosoproline (NPRO). In vitro,resorcinol, catechin, p-nitrosophenol and phenol were catalystsand chlorogenic acid an inhibitor; guaiacol showed a marginalcatalytic effect. Both the catalytic and the inhibiting effectswere dependent on pH and on the concentration of phenolic compounds;catalysis by resorcinol and catechin was increased at optimalratios of [nitrite]: [phenolic compound]. Endogenous nitrosationwas examined in vivo by co-administration of nitrite, prolineand a phenolic compound to rats and by monitoring the amountof NPRO excreted in the urine. Under similar experimental conditions,the catalytic effects observed in vivo decreased in the sameorder as those observed in vitro: resorcinol > p-nitrosophenol> catechin > phenol guaiacol; chlorogenic acid acted asan inhibitor. Catalysis and inhibition of N-nitrosation in ratsin vivo appears to occur via mechanisms similar to those invitro, although the effects in vivo were smaller. The implicationsof our findings for the endogenous formation of N-nitroso compoundsand for variations in exposure due to different dietary constituentsin humans are discussed.     

High prognostic value of p16INK4 alterations in gastrointestinal stromal tumors.

PURPOSE: Gastrointestinal stromal tumors (GISTs) represent a distinctive (but histologically heterogeneous) group of neoplasms, the malignant potential of which is often uncertain. To determine the prognostic relevance of p16INK4 alterations in GISTs, we investigated a larger group of GISTs and correlated the genetic findings with clinicopathological factors and patient survival. MATERIAL AND METHODS: We evaluated the methylation status of the promotor by methylation-specific polymerase chain reaction (PCR), the presence of mutations by PCR-SSCP-sequencing, the loss of heterozygosity at the p16INK4 locus (using the c5.1 marker), and the immunohistochemical expression of p16INK4 protein in 43 GISTs in 39 patients. RESULTS: p16INK4 alterations were found in 25 of 43 GISTs (58.1%), with benign, borderline, or malignant GISTs showing no differences in the type and frequency of alteration. p16INK4 alterations were correlated with a loss of p16INK4 protein expression (P <.01). Patients who had tumors with p16INK4 alterations had a poorer prognosis than patients with tumors without such alterations (P =.02). There was a high predictive value for p16INK4 alterations only in the group of benign and borderline GISTs (P <.01) with regard to clinical outcome. Univariate Cox's proportional hazard regression analysis revealed a strong correlation between p16INK4 alterations, tumor size, mitotic index, and overall survival (P <.02), whereas multivariate Cox's analysis confirmed only p16INK4 alterations as an independent prognostic factor. CONCLUSION: We believe that the evaluation of p16INK4 alteration status is a helpful prognosticator, particularly in the benign and borderline groups of GISTs.     

Phase I trial and pharmacokinetic study of BMS-247550, an epothilone B analog, administered intravenously on a daily schedule for five days.

PURPOSE: The epothilones are a novel class of nontaxane microtubule-stabilizing agents. BMS-247550 is a semisynthetic analog of the natural product epothilone B. We conducted a phase I study administering BMS-247550 as a 1-hour intravenous infusion daily for 5 consecutive days every 21 days. PATIENTS AND METHODS: Twenty-one patients received BMS-247550 without filgrastim in the first cycle. An additional six patients were enrolled at a starting dose of 8 mg/m2/d with filgrastim support. Twenty-one of the 27 patients had received prior paclitaxel, docetaxel, or both. RESULTS: One hundred seven cycles were administered to 27 patients. The maximum-tolerated dose was 6 mg/m2 of BMS-247550 administered as a 1-hour intravenous infusion daily for 5 consecutive days every 21 days. Dose-limiting toxicity at a dose of 8 mg/m2/d was neutropenia with or without filgrastim support. Nonhematologic grade 3 toxicities included fatigue (seven cycles), stomatitis (two cycles), and anorexia (one cycle). The mean terminal half-life of BMS-247550 was 16.8 +/- 6.0 hours, the volume of distribution at steady-state was 798 +/- 375 L, and the clearance was 712 +/- 247 mL/min. Objective responses were observed in patients with breast, cervical, and basal cell cancer. Reductions in CA-125 levels were noted in patients with ovarian cancer. CONCLUSION: The recommended phase II dose of BMS-247550 on the daily schedule for 5 days is 6 mg/m2/d. Neutropenia was dose limiting, but higher doses were tolerated by a large fraction of patients with filgrastim support. Peripheral neuropathy was mild, even after multiple cycles of therapy, and was not dose limiting.     

Morphologic dysplasia in de novo acute myeloid leukemia (AML) is related to unfavorable cytogenetics but has no independent prognostic relevance under the conditions of intensive induction therapy: results of a multiparameter analysis from the German AML Cooperative Group studies.

PURPOSE: On the basis of cytomorphology according to the French-American-British (FAB) classification, we evaluated the prognostic impact of dysplastic features and other parameters in de novo acute myeloid leukemia (AML). We also assessed the clinical significance of the recently introduced World Health Organization (WHO) classification for AML, which proposed dysplasia as a new parameter for classification. PATIENTS AND METHODS: We analyzed prospectively 614 patients with de novo AML, all of whom were diagnosed by central morphologic analysis and treated within the German AML Cooperative Group (AMLCG)-92 or the AMLCG-acute promyalocytic leukemia study. RESULTS: Patients with AML M3, M3v, or M4eo demonstrated a better outcome compared with all other FAB subtypes (P <.001); no prognostic difference was observed among other FAB subtypes. The presence or absence of dysplasia failed to demonstrate prognostic relevance. Other prognostic markers, such as age, cytogenetics, presence of Auer rods, and lactate dehydrogenase (LDH) level at diagnosis, all showed significant impact on overall and event-free survival in univariate analyses (P <.001 for all parameters tested). However, in a multivariate analysis, only cytogenetics (unfavorable or favorable), age, and high LDH maintained their prognostic impact. Dysplasia was not found to be an independent prognostic parameter, but the detection of trilineage dysplasia correlated with unfavorable cytogenetics. CONCLUSION: Our results indicate that cytomorphology and classification according to FAB criteria are still necessary for the diagnosis of AML but have no relevance for prognosis in addition to cytogenetics. Our results suggest that the WHO classification should be further developed by using cytogenetics as the main determinant of biology. Dysplastic features, in particular, have no additional impact on predicting prognosis when cytogenetics are taken into account.     

Family history of autoimmune thyroid disease and childhood acute leukemia.

The association between a familial history of autoimmune disease and childhood acute leukemia was investigated in a French case-control study that, overall, was designed to assess the role of perinatal, infectious, environmental, and genetic factors in the etiology of childhood acute leukemia. Familial histories of autoimmune disease in first- and second-degree relatives were compared in 279 incident cases, 240 cases of acute lymphocytic leukemia (ALL) and 39 cases of acute non-lymphoblastic leukemia (ANLL), and 285 controls. Recruitment was frequency matched by age, gender, hospital, and ethnic origin. Odds ratios (OR) were estimated using an unconditional regression model taking into account the stratification variables, socioeconomic status, and familial structure. A statistically significant association between a history of autoimmune disease in first- or second-degree relatives and ALL (OR, 1.7; 95% confidence interval (CI), 1.0-2.8) was found. A relationship between thyroid diseases overall and ALL (OR, 2.0; 95% CI, 1.0-3.9) was observed. This association was more pronounced for potentially autoimmune thyroid diseases (Grave's disease and/or hyperthyroidism and Hashimoto's disease and/or hypothyroidism) (OR, 3.5; 95% CI, 1.1-10.7 and OR, 5.6; 95% CI, 1.0-31.1, respectively for ALL and ANLL), whereas it was not statistically significant for the other thyroid diseases (thyroid goiter, thyroid nodule, and unspecified thyroid disorders) (OR, 1.6; 95% CI, 0.7-3.5 and OR, 1.3; 95% CI, 0.2-7.0, respectively, for ALL and ANLL). The results suggest that a familial history of autoimmune thyroid disease may be associated with childhood acute leukemia.     

Wait Times and Survival in Lung Cancer Patients across the Province of Quebec,Canada

Lung cancer is the leading cause of cancer death worldwide, with a five-year survival of 22% in Canada. Guidelines recommend rapid evaluation of patients with suspected lung cancer, but the impact on survival remains unclear. We reviewed medical records of all patients with newly diagnosed lung cancer in four hospital networks across the province of Quebec, Canada, between 1 February and 30 April 2017. Patients were followed for 3 years. Wait times for diagnosis and treatment were collected, and survival analysis using a Cox regression model was conducted. We included 1309 patients, of whom 39% had stage IV non-small cell lung cancer (NSCLC). Median wait times were, in general, significantly shorter in patients with stage III–IV NSCLC or SCLC. Surgery was associated with delays compared to other types of treatments. Median survival was 12.9 (11.1–15.7) months. The multivariate survival model included age, female sex, performance status, histology and stage, treatment, and the time interval between diagnosis and treatment. Longer wait times had a slightly protective to neutral effect on survival, but this was not significant in the stage I–II NSCLC subgroup. Wait times for the diagnosis and treatment of lung cancer were generally within targets. The shorter wait times observed for advanced NSCLC and SCLC might indicate a tendency for clinicians to act quicker on sicker patients. This study did not demonstrate the detrimental effect of longer wait times on survival.     

Sulfemodin 8-O-beta-D-glucoside,a new sulfated anthraquinone glycoside,and antioxidant phenolic compounds from Rheum emodi

A sulfated emodin glucoside, emodin 8-O-beta-D-glucopyranosyl-6-O-sulfate (1), was isolated from the roots of Rheum emodi in an investigation of the active constituents of this Nepalese medicinal plant, and its structure was determined by spectroscopic and chemical methods. Additionally, two rare auronols, carpusin (2) and maesopsin (3), besides other anthraquinones and phenolics, were isolated and identified. Compounds 2 and 3 showed significant antioxidant activity in the DPPH assay, while chrysophanol, physcion, and emodin and their 8-O-glucosides were found to be inactive.     

Midbrain syndrome with eye movement disorder: dramatic improvement after cranioplasty

BACKGROUND Patients with skull defects sometimes develop neurological deficits, which have been grouped under “the syndrome of the trephined”. The deficits are usually nonspecific or nonlocalizing, such as apathy or diffuse headaches. We report, to our knowledge, a first case of severe midbrain syndrome associated with a skull defect. Cranioplasty dramatically resolved the patient's symptoms. A midbrain syndrome represents the main manifestation of the syndrome of the trephined and can be corrected by cranioplasty. CLINICAL PRESENTATION A 38-year-old man with head trauma and epidural hematoma initially had normal eye motility. He developed a skull defect after infection following cranioplasty. He presented with onset of neurological symptoms one year after head trauma with a skull defect, a small divergent and vertical strabismus, elevation deficit of both eyes, headaches and fatigue. Over several months he developed severe bilateral deficit of adduction, elevation, depression and convergence. He had neuropsychological deficits, fatigue, headaches and impaired coordination. Neuroimaging and lumbar puncture did not show evidence of increased intracranial pressure or hydrocephalus. INTERVENTION Cranioplasty using Palacos was performed one-and-a-half years after trauma. Immediately after surgery, the patient noted remarkable improvement in his symptoms. Headaches and fatigue disappeared within two days. Two weeks after cranioplasty the patient had orthotropia and virtually normal ocular motility. Neurological symptoms completely disappeared. Recovery remained sustained for over 5 years after cranioplasty. CONCLUSION To our knowledge, this represents the first case of the syndrome of the trephined in which the neurological deficits map primarily to the brainstem and show rapid improvement following cranioplasty. We show that cranioplasty in patients with large skull defects is indicated for more then cosmetic reasons and should be considered even after longer periods following a trauma.     

An auto-controlled prospective comparison of two embryos culture media (G III series versus ISM) for IVF and ICSI treatments

Purpose

To compare the effects of 2 different media on embryo morphology and development at days 2/3.

Method

Six hundred seventy-six attempts from 512 couples were included in this prospective auto-controlled study. Sibling oocytes of all couples undergoing an IVF (n?=?286) or ICSI (n?=?390) attempt were randomly assigned to either GIII series (Vitrolife) or ISM (Medicult) media. Primary end points were fertilization and embryo morphology rates.

Results

Fertilization rates in GIII series and ISM (IVF: 59.9 vs 62.0% and ICSI: 65.7 vs 66.8%) respectively were not different. GIII series showed an increase, compared to ISM, of early cleavage rate, (IVF: 25.8 vs 16.2% (p?=?0.005); ICSI: 40.8 vs 25.5% (p?<?0.0001), and good embryo morphology rate at day 2 [IVF: 64.6 vs 57.3% (p?=?0.01); ICSI: 74.2 vs 69.4 (p?=?0.03)] and at day 3 [IVF: 57.5 vs 49.0% (p?=?0.02); ICSI: 67.2 vs 61.6% (p?=?0.01)].

Conclusions

Embryo morphology at days 2/3 was significantly enhanced when the embryos were cultured in GIII series.