嘉陵江小三峡硅藻群落结构及水环境

为了研究嘉陵江小三峡硅藻群落结构及水质状况,按枯水期（2006年11月—2007年3月）、平水期（2007年4—6月）和丰水期（2007年7—9月）分别采集6个样点的硅藻样品,分析其物种组成、细胞密度、多样性和均匀度指数及硅藻商等,并结合理化指标对水质进行评价。结果表明：嘉陵江小三峡共有硅藻78种（含变种和变型）,隶属2纲、10科、20属;硅藻细胞密度为0.53×10⁴～3.58×10⁴ ind·L^-1,总平均1.55×10⁴ ind·L^-1;多样性指数值（H′）为1.62～2.96,总平均2.33;均匀度指数值（E）为0.28～0.56,总平均0.42;嘉陵江小三峡水质总体上属β-中污水体,沙溪、北温泉水质较好,属微污水体,碚石、牛石沱水质次之,为β-中污水体,盐井、毛背沱水质最差,为α-中污水体。     

Renal FNA-based typing of renal masses remains a useful adjunctive modality: evaluation of 31 renal masses with correlative histology

Objectives:  Given the advances in renal imaging modalities in the recent years, a greater number of renal cell carcinomas (RCCs) with tumour size of <3 cm are being detected radiologically. Consequently, there is a pressing need for accurate typing of RCCs which, in turn, will aid in selection of cases of nephron-sparing surgery.
Methods:  A total of 31 cases of renal masses with available fine needle aspiration (FNA) material and concomitant histopathology details were retrieved. They included 27 RCCs (17 clear cells, eight papillary and two chromophobe), one oncocytoma, one liposarcoma and two benign lesions – one xanthogranulomatous pyelonephritis (XPN) and one benign cyst. Two investigators reviewed all FNA material. The degree of concordance between cytological typing and histological typing was assessed.
Results:  There was excellent agreement between the FNA typing and the final diagnosis, with correct classification in 28 of 31 cases. Among the three discordant cases, two were RCCs. The first was a papillary RCC (PRCC) that was misdiagnosed on FNA as clear cell RCC. Another case that was typed as a PRCC on final histopathology was diagnosed 'suspicious cells' on FNA. The third case was an XPN that was misdiagnosed on FNA as RCC with necrosis.
Conclusions:  There is an excellent concordance (90.3%) between the FNA diagnosis and the final histological diagnosis, especially in RCCs. There is a tendency for misdiagnosis with PRCC. Lesions with extensive necrosis and relatively insufficient diagnostic material on FNA specimens must be interpreted with caution. Better concordance might be observed with more extensive sampling.     

Extension of the SAEM algorithm for nonlinear mixed models with 2 levels of random effects

This article focuses on parameter estimation of multilevel nonlinearmixed-effects models (MNLMEMs). These models are used to analyzedata presenting multiple hierarchical levels of grouping (clusterdata, clinical trials with several observation periods, ...).The variability of the individual parameters of the regressionfunction is thus decomposed as a between-subject variabilityand higher levels of variability (e.g. within-subject variability).We propose maximum likelihood estimates of parameters of thoseMNLMEMs with 2 levels of random effects, using an extensionof the stochastic approximation version of expectation–maximization(SAEM)–Monte Carlo Markov chain algorithm. The extendedSAEM algorithm is split into an explicit direct expectation–maximization(EM) algorithm and a stochastic EM part. Compared to the originalalgorithm, additional sufficient statistics have to be approximatedby relying on the conditional distribution of the second levelof random effects. This estimation method is evaluated on pharmacokineticcrossover simulated trials, mimicking theophylline concentrationdata. Results obtained on those data sets with either the SAEMalgorithm or the first-order conditional estimates (FOCE) algorithm(implemented in the nlme function of R software) are compared:biases and root mean square errors of almost all the SAEM estimatesare smaller than the FOCE ones. Finally, we apply the extendedSAEM algorithm to analyze the pharmacokinetic interaction oftenofovir on atazanavir, a novel protease inhibitor, from theAgence Nationale de Recherche sur le Sida 107-Puzzle 2 study.A significant decrease of the area under the curve of atazanaviris found in patients receiving both treatments.     

Statistical Identifiability and the Surrogate Endpoint Problem,with Application to Vaccine Trials

Summary Given a randomized treatment Z, a clinical outcome Y, and a biomarker S measured some fixed time after Z is administered, we may be interested in addressing the surrogate endpoint problem by evaluating whether S can be used to reliably predict the effect of Z on Y. Several recent proposals for the statistical evaluation of surrogate value have been based on the framework of principal stratification. In this article, we consider two principal stratification estimands: joint risks and marginal risks. Joint risks measure causal associations (CAs) of treatment effects on S and Y, providing insight into the surrogate value of the biomarker, but are not statistically identifiable from vaccine trial data. Although marginal risks do not measure CAs of treatment effects, they nevertheless provide guidance for future research, and we describe a data collection scheme and assumptions under which the marginal risks are statistically identifiable. We show how different sets of assumptions affect the identifiability of these estimands; in particular, we depart from previous work by considering the consequences of relaxing the assumption of no individual treatment effects on Y before S is measured. Based on algebraic relationships between joint and marginal risks, we propose a sensitivity analysis approach for assessment of surrogate value, and show that in many cases the surrogate value of a biomarker may be hard to establish, even when the sample size is large.     

Informed consent in clinical research at a general hospital in Mexico: opinions of the investigators

In Mexico informed consent is a legal requirement that ensures that patients who are invited to participate in clinical trials are provided with all the information needed to decide whether to participate, or not, in a research protocol. To improve our understanding of the problems physicians in developing countries encounter, when obtaining informed consent (IC), we examined their opinion on the importance of IC in clinical research, the quantity and quality of the information provided to the participant, and the conditions in which the IC is obtained. Investigators considered that IC was useful to the patients, providing information that helped the patient to make a decision about his/her participation. Nevertheless, they felt that for some aspects of the research, like drug development in general, the use of placebos, and the randomization process, many of the patients were not capable of fully understanding the information provided, referring to the complexity of the information and illiteracy as the main reasons. Many investigators were not acquainted with some of the guidelines established in the Mexican General Law of Health,(1) 36% of them admitting to not having completed their IC letters. Most investigators gave only minutes to the patient to make a decision and 20% of ICs were obtained while the patient was hospitalized. Except for one investigator, all of them considered that specific training in medical ethics would be useful for the daily clinical work.     

Dietary macronutrients influence 13C and 15N signatures of pinnipeds: captive feeding studies with harbor seals (Phoca vitulina)

Metabolic effects of dietary macronutrients on diet-tissue isotopic discrimination factors were investigated in harbor seals. Three seals were fed either high fat/low protein herring (H), or low fat/high protein pollock (P), and switched to the alternative every 4 months. This allowed each seal to be subjected to two dietary treatments in each of three metabolically defined seasons (breeding from May to September, molting from September to January, and late winter/early spring period from January to May) over a 2 year cycle, and function as its internal control regardless of physiological changes over season. One seal was fed a constant equal mix of H and P over the entire trial. Up to 1 per thousand differences in serum delta15N values of one seal fed alternatively on H and P were observed. Progressively more enriched serum delta15N values as diet switching from H to P might link to changes in seal digestive physiology and protein metabolism in response to very high protein intake on P diet. These findings demonstrate that dietary macronutrients of prey species and protein intake level of consumers also play important roles in shaping isotopic patterns of a consumer's tissues, and thus influence accurate data interpretation of stable isotope techniques in ecological applications.     

Gene therapy. An ethical profile of a new medical territory

From early on, the possibility of genetic intervention in humans has been the subject of philosophical and ethical reflection in the scientific community. It became the object of public debate and parliamentary decision‐making under the rule of law even before the first authorized trials on human subjects could start. This article explains why the debate on germ‐line intervention and genetic enhancement is still ongoing. The focus is on somatic gene therapy. There is a political and academic consensus that it represents an adequate tool for a high‐ranking end if some points are considered and taken into account. But where do we stand and what are the ethical conclusions we can draw from recent clinical experiences? Copyright © 2006 John Wiley & Sons, Ltd.     

Is it going to be SIN?

Insertional mutagenesis resulting in a leukaemia-like lymphoproliferative disease, as observed in the X-SCID (severe combined immunodeficiency) clinical trial using a gamma-retroviral vector that transferred a functional copy of the defective gene into hematopoietic precursor cells of affected children, sparked a debate about a ban on conventional gamma-retroviral vectors. This commentary summarizes the relevant data on this topic and concludes that there is no preclinical or clinical evidence as yet that SIN vectors, which self-inactivate the retroviral long terminal repeats (LTRs), will indeed show an improved safety profile. Conventional murine leukaemia virus (MLV) vectors can thus be used further in clinical gene therapy trials but require a thorough case-by-case risk-benefit analysis.     

Type II fish antifreeze protein accumulation in transgenic tobacco does not confer frost resistance

Type II fish antifreeze protein (AFP) is active in both freezing point depression and the inhibition of ice recrystallization. This extensively disulfidebonded 14 kDa protein was targeted for accumulation in its pro and mature forms in the cytosol and apoplast of transgenic tobacco plants. Type II AFP gene constructs under control of a duplicate cauliflower mosaic virus 35S promoter, both with and without a native plant transit peptide sequence, were introduced into tobacco by Agrobacterium tumefaciensmediated transformation. AFP did not accumulate in the cytosol of transgenic plants, but active AFP was present as 2% of the total protein present in the apoplast. Plantproduced AFP was the same size as mature Type II AFP isolated from fish, and was comparable to wildtype AFP in thermal hysteresis activity and its effect on ice crystal morphology. Field trials conducted in late summer on R1 generation transgenic plants showed similar AFP accumulation in plants under field conditions at levels suitable for largescale production: but no difference in frost resistance was observed between transgenic and wildtype plants during the onset of early fall frosts.     

Validation of surrogate markers in multiple randomized clinical trials with repeated measurements: canonical correlation approach

Part of the recent literature on the evaluation of biomarkers as surrogate endpoints starts from a multitrial context, which leads to a definition of validity in terms of the quality of both trial-level and individual-level association between the surrogate and true endpoints (Buyse et al., 2000, Biostatistics1, 49-67). These authors concentrated on cross-sectional continuous responses. However, in many randomized clinical studies, repeated measurements are encountered on either or both endpoints. A challenge in this setting is the formulation of a simple and meaningful concept of "surrogacy."Alonso et al. (2003, Biometrical Journal45, 931-945) proposed the variance reduction factor (VRF) to evaluate surrogacy at the individual level. They also showed how and when this concept should be extended to study surrogacy at the trial level. Here, we approach the problem from the natural canonical correlation perspective. We define a class of canonical correlation functions that can be used to study surrogacy at the trial and individual level. We show that the VRF and the R2 measure defined by Buyse et al. (2000) follow as special cases. Simulations are conducted to evaluate the performance of different members of this family. The methodology is illustrated on data from a meta-analysis of five clinical trials comparing antipsychotic agents for the treatment of chronic schizophrenia.