Structures et propriétés diélectriques des poly(α-acétoxystyréne)s parasubstitués

The relations between structure and isothermal, dielectric properties of poly(α-acetoxystyrene)s substituted in para position by ? OCOCH₃ ( 1a ), ? OCOCH₂CH₃ ( 1b ), ? OCOCH₂CH₂CH₃ ( 1c ), ? OCOC₆H₅ ( 1d ), ? OCOCH₂CH₂Cl ( 1f ) and ? OCOOCH₃ ( 1g ) were studied. The dielectric constants, at 10⁵ Hz and 20 ± 2°C, were found to be: 3,79 ( 1a ), 3,36 ( 1b ), 3,18 ( 1c ), 3,51 ( 1d ), 3,36 ( 1e ), 3,65 ( 1f ) and 3,07 ( 1g ). The polymers 1a – 1g do not show any α- or β-transition. Increasing bulkiness of the para substituent gives rise to a decreasing dielectric constant due to an increase of the degree of syndiotacticity, as determined from ¹H and ¹³C NMR spectra.     

Quantitation of differential sensitivity of normal marrow myeloid progenitor cells to anthracene derivatives

The effect of 3 anthracene derivatives, mitoxantrone, ametantrone, bisantrene, on 4 normal human bone marrows, was studied using the myeloid stem cell assay developed by Pike and Robinson, in order to define to what extent this test could be used to predict the relative clinical hematologic toxicity of new anticancer agents. For the 3 drugs, an exponential relationship between colony survival and drug concentration was found, but was much steeper for mitoxantrone (slope = -195.2 ± 8.8/g/ml) than for ametantrone (slope = 5.1 ± 1.0/g/ml, p0.001) and bisantrene (slope = 7.1 ± 0.3/g/ml, p0.001). The difference of slope between ametantrone and bisantrene was of borderline significance (p0.05). The ratios of concentrations inducing a 50% growth inhibition for mitoxantrone versus bisantrene and for ametantrone versus bisantrene were close to the corresponding ratios of concentrations inducing a 90% growth inhibition. The relative in vitro toxicities reproduce very well the relative myelosuppression observed in clinical trials with mitoxantrone versus bisantrene but the results were less satisfactory for the comparison of these 2 agents with ametantrone. In addition, our data suggest that, for these 3 compounds, intrinsic myeloid progenitor sensitivity is a major determinant of leukopenia.     

Lumbar degenerative spondylolisthesis: factors associated with the decision to fuse

BACKGROUND CONTEXTThe indication to perform a fusion and decompression surgery as opposed to decompression alone for lumbar degenerative spondylolisthesis (LDS) remains controversial. A variety of factors are considered when deciding on whether to fuse, including patient demographics, radiographic parameters, and symptom presentation. Likely surgeon preference has an important influence as well.PURPOSEThe aim of this study was to assess factors associated with the decision of a Canadian academic spine surgeon to perform a fusion for LDS.STUDY DESIGN/SETTINGThis study is a retrospective analysis of patients prospectively enrolled in a multicenter Canadian study that was designed to evaluate the assessment and surgical management of LDS.PATIENT SAMPLEInclusion criteria were patients with: radiographic evidence of LDS and neurogenic claudication or radicular pain, undergoing posterior decompression alone or posterior decompression and fusion, performed in one of seven, participating academic centers from 2015 to 2019.OUTCOME MEASURESPatient demographics, patient-rated outcome measures (Oswestry Disability Index [ODI], numberical rating scale back pain and leg pain, SF-12), and imaging parameters were recorded in the Canadian Spine Outcomes Research Network (CSORN) database. Surgeon factors were retrieved by survey of each participating surgeon and then linked to their specific patients within the database.METHODSUnivariate analysis was used to compare patient characteristics, imaging measures, and surgeon variables between those that had a fusion and those that had decompression alone. Multivariate backward logistic regression was used to identify the best combination of factors associated with the decision to perform a fusion.RESULTSThis study includes 241 consecutively enrolled patients receiving surgery from 11 surgeons at 7 sites. Patients that had a fusion were younger (65.3±8.3 vs. 68.6±9.7 years, p=.012), had worse ODI scores (45.9±14.7 vs. 40.2±13.5, p=.007), a smaller average disc height (6.1±2.7 vs. 8.0±7.3 mm, p=.005), were more likely to have grade II spondylolisthesis (31% vs. 14%, p=.008), facet distraction (34% vs. 60%, p=.034), and a nonlordotic disc angle (26% vs. 17%, p=.038). The rate of fusion varied by individual surgeon and practice location (p<.001, respectively). Surgeons that were fellowship trained in Canada more frequently fused than those who fellowship trained outside of Canada (76% vs. 57%, p=.027). Surgeons on salary fused more frequently than surgeons remunerated by fee-for-service (80% vs. 64%, p=.004). In the multivariate analysis the clinical factors associated with an increased odds of fusion were decreasing age, decreasing disc height, and increasing ODI score; the radiographic factors were grade II spondylolisthesis and neutral or kyphotic standing disc type; and the surgeon factors were fellowship location, renumeration type and practice region. The odds of having a fusion surgery was more than two times greater for patients with a grade II spondylolisthesis or neutral and/or kyphotic standing disc type (opposed to lordotic standing disc type). Patients whose surgeon completed their fellowship in Canada, or whose surgeon was salaried (opposed to fee-for-service), or whose surgeon practiced in western Canada had twice the odds of having fusion surgery.CONCLUSIONSThe decision to perform a fusion in addition to decompression for LDS is multifactorial. Although patient and radiographic parameters are important in the decision-making process, multiple surgeon factors are associated with the preference of a Canadian spine surgeon to perform a fusion for LDS. Future work is necessary to decrease treatment variability between surgeons and help facilitate the implementation of evidence-based decision making.     

Ten‐year attrition and antiretroviral therapy response among HIV‐positive adults: a sex‐based cohort analysis from eight West African countries

IntroductionSex differences have already been reported in sub‐Saharan Africa for attrition and immunological response after antiretroviral therapy (ART) initiation, but follow‐up was usually limited to the first two to three years after ART initiation. We evaluated sex differences on the same outcomes in the 10 years following ART initiation in West African adults.MethodsWe used cohort data of patients included in the IeDEA West Africa collaboration, who initiated ART between 2002 and 2014. We modelled no‐follow‐up and 10‐year attrition risks, and immunological response by sex using logistic regression analysis, survival analysis with random effect and linear mixed models respectively.ResultsA total of 71,283 patients (65.8% women) contributed to 310,007 person‐years of follow‐up in 16 clinics in eight West African countries. The cumulative attrition incidence at 10‐year after ART initiation reached 75% and 68% for men and women respectively. Being male was associated with an increased risk of no follow‐up after starting ART (5.1% vs. 4.0%, adjusted Odds Ratio: 1.25 [95% CI: 1.15 to 1.35]) and of 10‐year attrition throughout the 10‐year period following ART initiation: adjusted Hazard Ratios were 1.22 [95% CI: 1.17 to 1.27], 1.08 [95% CI: 1.04 to 1.12] and 1.04 [95% CI: 1.01 to 1.08] during year 1, years 2 to 4 and 5 to 10 respectively. A better immunological response was achieved by women than men: monthly CD4 gain was 30.2 and 28.3 cells/mL in the first four months and 2.6 and 1.9 cells/μL thereafter. Ultimately, women reached the average threshold of 500 CD4 cells/μL in their sixth year of follow‐up, whereas men failed to reach it even at the end of the 10‐year follow‐up period. The proportion of patients reaching the threshold was much higher in women than in men after 10 years since ART initiation (65% vs. 44%).ConclusionsIn West Africa, attrition is unacceptably high in both sexes. Men are more vulnerable than women on both attrition and immunological response to ART in the 10 years following ART initiation. Innovative tracing strategies that are sex‐adapted are needed for patients in care to monitor attrition, detect early high‐risk groups so that they can stay in care with a durably controlled infection.     

Thiamin deficiency in HIV-positive patients: evaluation by erythrocyte transketolase activity and thiamin pyrophosphate effect

BACKGROUND AND AIMS: The aim of the study was to determine the thiamin status in HIV-positive patients. METHODS: Measurement of erythrocyte transketolase activity (ETK) and thiaminpyrophosphate (TPP) effect in 55 consecutive HIV-positive patients of a specialized outpatient clinic were grouped into five groups according to their CD4 counts. Comparison of results of HIV-positive patients with age-matched control group of 22 healthy subjects. RESULTS: Of the patients, 27% had a pathologically-increased TPP effect, 18% of the patients had pathologically-low ETK. The percentage of pathological values of TPP effect in the patients was significantly higher compared with the control group. There was no statistically significant correlation between pathological thiamin status and stage of the disease, zidovudine therapy or nutritional status of the patients. CONCLUSIONS: Thiamin deficiency in HIV-positive patients was found in a higher percentage than previously reported. Thiamine deficiency is not only present in advanced stages of HIV-infection, but also in clinically asymptomatic patients.     

Evaluation of whole blood catalase estimation for diagnosis of malignancy

Whole blood catalase levels were estimated using a disc flotation method in 209 random patients with a wide variety of malignancies. Fifty patients had received no treatment, and the remainder, although having undergone prior therapy, had recurrent or metastatic disease at the time of the study. No relationship was found between the presence of cancer and catalase levels. A direct relationship was found for catalase with hemoglobin levels in both normal and patients' samples. Whole blood catalase is of no value in diagnosis and monitoring of cancer. The decreased catalase values found here and reported previously by others are the result of low hemoglobin levels found in many patients with cancer.     

Downregulation of neuronal cdk5/p35 in opioid addicts and opiate-treated rats: relation to neurofilament phosphorylation.

Neuronal cyclin-dependent kinase-5 (Cdk5) and its neuron-specific activator p35 play a major role in regulating the cytoskeleton dynamics. Since opioid addiction was associated with hyperphosphorylation of neurofilament (NF) in postmortem human brains, this study was undertaken to assess the status of the cdk5/p35 complex and its relation with NF-H phosphorylation in brains of chronic opioid abusers. Decreased immunodensities of cdk5 (18%) and p35 (26-44%) were found in the prefrontal cortex of opioid addicts compared with matched controls. In the same brains, the densities of p25 (a truncated neurotoxic form of p35), phosphatase PP2Ac and mu-calpain were found unaltered. Acute treatment of rats with morphine (30 mg/kg, 2 h) increased the density of cdk5 (35%), but not that of p35, in the cerebral cortex. In contrast, chronic morphine (10-100 mg/kg for 5 days) induced marked decreases in cdk5 (40%) and p35 (47%) in rat brain. In brains of opioid addicts, the density of phosphorylated NF-H was increased (43%) as well as the ratio of phosphorylated to nonphosphorylated NF-H forms (two-fold). In these brains, phosphorylated NF-H significantly correlated with p35 (r=0.58) but not with cdk5 (r=0.03). The results suggest that opiate addiction is associated with downregulation of cdk5/p35 levels in the brain. This downregulation and the aberrant hyperphosphorylation of NF-H proteins might have important consequences in the development of neural plasticity associated with opiate addiction in humans.     

In vivo imaging of apoptosis by 99mTc-Annexin V scintigraphy: visual analysis in relation to treatment response.

BACKGROUND AND PURPOSE: Anticancer therapy induces apoptosis in a dose- and time-dependent fashion. (99m)Tc-Hynic-rh-Annexin V scintigraphy (TAVS) enables non-invasive in vivo imaging of treatment-induced apoptosis. We identified the visual patterns of (99m)Tc-Hynic-rh-Annexin V tumour uptake and related these to treatment response. PATIENTS AND METHODS: Thirty-three patients with malignant lymphoma (n=26), leukaemia (n=1) NSCLC (n=5), H&NSCC (n=1), scheduled for radiotherapy (n=27), platinum-based chemotherapy (n=5) or concurrent chemoradiation (n=1), underwent TAVS before and early after the start of treatment. Planar and SPECT images were visually examined to assess changes in tumour (99m)Tc-Hynic-rh-Annexin V uptake. Twenty-nine patients were eligible for further analysis. Annexin V uptake before (U(baseline)) and early after (U(post)) the start of treatment was graded using a four-step scale: 0, absent; 1, weak; 2, moderate and 3, intense. The difference between these values (Delta U) was calculated and correlated to tumour response after therapy (Spearman rank correlation test). RESULTS: Weak to moderate U(baseline) was detected in 13/15 patients with a complete response and U(post) was markedly increased in all these cases (Delta U range 1-3). Partial response (n=7) was associated with weak to moderate U(baseline) and a moderately increased U(post) (Delta U range 1-2). In patients with stable disease (n=5), U(baseline) was predominantly weak, without considerable changes in uptake after the start of treatment (Delta U range 0-1). Finally, in case of progressive disease (n=2), either no tumour uptake or a decrease in U(post) was detected (Delta U=-1). A statistically significant correlation was found between changes in (99m)Tc-Hynic-rh-Annexin V tumour uptake and clinical response (correlation coefficient=0.62; P<0.001). CONCLUSIONS: Complete or partial tumour response was associated with a marked increase of (99m)Tc Hynic-rh-Annexin V accumulation early during treatment compared to baseline values. In case of stable or progressive disease, pretreatment scans demonstrated predominantly low (99m)Tc Hynic-rh-Annexin V tumour uptake and no significant increase early after treatment. These results indicate that TAVS might be useful as a predictive test for treatment response.     

Liposomal irinotecan: formulation development and therapeutic assessment in murine xenograft models of colorectal cancer.

PURPOSE: The purpose is to demonstrate whether an appropriately designed liposomal formulation of irinotecan is effective in treating mice with liver-localized colorectal carcinomas. EXPERIMENTAL DESIGN: Irinotecan was encapsulated in 1,2-distearoyl-sn-glycero-3-phosphocholine/cholesterol (55:45 molar ratio) liposomes using an ionophore (A23187)-generated transmembrane proton gradient. This formulation was evaluated in vivo by measuring plasma elimination of liposomal lipid and drug after i.v. administration. Therapeutic activity was determined in SCID/Rag-2M mice bearing s.c. LS180 tumors or orthotopic LS174T colorectal metastases. RESULTS: Drug elimination from the plasma was significantly reduced when irinotecan was administered in the liposomal formulation. At 1 hour after i.v. administration, circulating levels of the liposomal drug were 100-fold greater than that of irinotecan given at the same dose. High-performance liquid chromatographic analysis of plasma samples indicated that liposomal irinotecan was protected from inactivating hydrolysis to the carboxylate form. This formulation exhibited substantially improved therapeutic effects. For the LS180 solid tumor model, it was shown that after a single injection of liposomal irinotecan at 50 mg/kg, the time to progress to a 400-mg tumor was 34 days (as compared with 22 days for animals treated with free drug at an equivalent dose). In the model of colorectal liver metastases (LS174T), a median survival time of 79 days was observed after treatment with liposomal irinotecan (50 mg/kg, given every 4 days for a total of three doses). Saline and free drug treated mice survived for 34 and 53 days, respectively. CONCLUSIONS: These results illustrate that liposomal encapsulation can substantially enhance the therapeutic activity of irinotecan and emphasize the potential for using liposomal irinotecan to treat liver metastases.     

Radiation-Induced Apoptosis: The Ceramide-SAPK Signaling Pathway and Clinical Aspects

Apoptosis, or programmed cell death is an important regulatory mechanism that is involved in a variety of homeostatic processes. Decreased cellular sensitivity or inappropriate responses to apoptotic stimuli may be important factors in tumorigenesis and resistance to anticancer treatments. It is generally accepted that all mammalian cells constitutively express the biochemical machinery to execute apoptosis. It is, however, not clear which signal transduction pathways are involved, or to which extent various stimuli activate independent or partially overlapping pathways. In this paper we discuss the involvement of a ceramide-mediated stress-activated protein kinase (SAPK) signaling cascade in radiation-induced apoptosis. Furthermore, examples are presented of pharmacological intervention in specific signal transduction pathways that lead to modulation of the apoptotic response. Finally, data are presented to illustrate the potential clinical relevance of apoptosis.