Concordance of Pre-Operative Clinical Stage With Pathologic Stage In Patients ≥45 Years Old With Well-Differentiated Thyroid Cancer

Objective: Clinical stage (cStage) in thyroid cancer determines extent of surgical therapy and completeness of resection. Pathologic stage (pStage) is an important determinant of outcome. The rate of discordance between clinical and pathologic stage in thyroid cancer is unknown.Methods: The National Cancer Data Base was queried to identify 27,473 patients ≥45 years old with cStage I through IV differentiated thyroid cancer undergoing surgery from 2008–2012.Results: There were 16,286 (59.3%) cStage I patients; 4,825 (17.6%) cStage II; 4,329 (15.8%) cStage III; and 2,013 (7.3%) cStage IV patients. The upstage rate was 15.1%, and the downstage rate was 4.6%. For cStage II, there was a 25.5% upstage rate. The change in cStage was a result of inaccurate T-category in 40.8%, N-category in 36.3%, and both in 22.9%. On multivariate analysis, the patients more likely to be upstaged had papillary histology, tumors 2.1 to 4 cm, total thyroidectomy, nodal surgery, positive margins, or multifocal disease. Upstaged patients received radioiodine more frequently (75.3% vs. 48.1%; P<.001).Conclusion: Approximately 20% of cStage is discordant to pStage. Certain populations are at risk for inaccurate staging, including cT2 and cN0 patients. Upstaged patients are more likely to receive radioactive iodine therapy.Abbreviations: CI = confidence interval; cStage = clinical stage; DTC = differentiated thyroid cancer; NCDB = National Cancer Data Base; OR = odds ratio; pStage = pathologic stage; RAI = radioactive iodine     

Nonparametric Bayesian Variable Selection With Applications to Multiple Quantitative Trait Loci Mapping With Epistasis and Gene–Environment Interaction

The joint action of multiple genes is an important source of variation for complex traits and human diseases. However, mapping genes with epistatic effects and gene–environment interactions is a difficult problem because of relatively small sample sizes and very large parameter spaces for quantitative trait locus models that include such interactions. Here we present a nonparametric Bayesian method to map multiple quantitative trait loci (QTL) by considering epistatic and gene–environment interactions. The proposed method is not restricted to pairwise interactions among genes, as is typically done in parametric QTL analysis. Rather than modeling each main and interaction term explicitly, our nonparametric Bayesian method measures the importance of each QTL, irrespective of whether it is mostly due to a main effect or due to some interaction effect(s), via an unspecified function of the genotypes at all candidate QTL. A Gaussian process prior is assigned to this unknown function. In addition to the candidate QTL, nongenetic factors and covariates, such as age, gender, and environmental conditions, can also be included in the unspecified function. The importance of each genetic factor (QTL) and each nongenetic factor/covariate included in the function is estimated by a single hyperparameter, which enters the covariance function and captures any main or interaction effect associated with a given factor/covariate. An initial evaluation of the performance of the proposed method is obtained via analysis of simulated and real data.TRAITS showing continuous variation are called quantitative traits and are typically controlled by multiple genetic and nongenetic factors, which tend to have relatively small effects individually. Crosses between inbred lines produce suitable populations for quantitative trait locus (QTL) mapping and are available for agricultural plants and for animal (e.g., mouse) models of human diseases. Such crosses are often used to detect QTL. For these inbred line crosses, uniform genetic backgrounds, controlled breeding schemes, and controlled environment ensure that there is little or no confounding of uncontrolled sources of variability with genetic effects. The potential for such confounding complicates and limits the analysis and interpretation of human data. Because of the homology between humans and rodents, rodent models can be extremely useful in advancing our understanding of certain human diseases. In the past 2 decades, various statistical approaches have been developed to identify QTL in inbred line crosses (see, for example, Doerge et al. 1997 for review). To perform QTL mapping (identification), a large number of candidate positions (candidate QTL) along the genome are selected. These candidate QTL may all be located at genetic markers (positions of sequence variants in the genome where the genotypes of all individuals in a mapping population can be measured) or also in between markers if the marker density is not high. QTL mapping may then be performed by considering one candidate QTL at a time or multiple candidate QTL simultaneously. For inbred line crosses with low marker density and considering a single candidate QTL at a time, the interval-mapping method was proposed by Lander and Botstein (1989). However, these authors showed that interval mapping tends to identify a “ghost” QTL located in between two actual linked QTL if two or more closely linked QTL exist. This problem can be reduced or eliminated in two ways: (1) by using composite-interval mapping (Jansen and Stam 1994; Zeng 1994) which still performs a one-dimensional QTL search but conditional on the genotypes at a pair of markers flanking the marker interval containing the current QTL, to absorb the effects of background (nontarget QTL) outside of the target interval; or (2) by performing multiple QTL mapping, where two or more QTL are mapped simultaneously. Furthermore, if several QTL affect a quantitative trait mostly through their interactions (epistasis) while having nonexistent or weak main effects, then interval mapping or single-marker analysis will fail to detect such QTL. QTL interactions may not be limited to pairwise interactions. Marchini et al. (2005) have shown by simulation that searching for three loci jointly in the presence of a three-way interaction is more powerful than searching for a single or a pair of QTL. There are various different implementations of multiple QTL mapping. Most methods still perform only pairwise searches, with and without epistasis. The most recent methods are based on Bayesian variable selection and consider a group of candidate QTL or all candidate QTL in the genome simultaneously (e.g., Yi et al. 2007). These methods are typically still limited to pairwise interactions among QTL and do not consider gene–environment interactions.The identification of QTL can be viewed as a very large variable selection problem: for p candidate QTL, with p typically in the hundreds or thousands and sample size in the low hundreds, there are 2^p possible main-effect models, possible two-way interactions, and possible higher-order (k > 2) interactions. For inbred line crosses, where multiple-QTL mapping models can be represented as multiple linear regression models, classical variable selection methods such as forward and stepwise selection (Broman and Speed 2002) have been used in searching for main and two-way interaction effects. Bayesian analysis implemented by Markov chain Monte Carlo (MCMC) and based on the composite model space framework (Godsill 2001, 2003) has been introduced to genetic mapping (Yi 2004). Well-known Bayesian variable selection methods such as reversible jump MCMC (Green 1995) and stochastic search variable selection (SSVS) (George and McCulloch 1993) are special cases. SSVS and similar methods employ mixture priors for the regression coefficients, which specify different distributions for the coefficients under the null (effect negligible) and alternative (effect nonnegligible) hypotheses. The marginal posterior probabilities of the alternative hypotheses can be used to identify a subset of important parameters on the basis of Bayesian multiple comparison rules, including the median probability model (with a threshold of 0.5) and Bayesian false discovery rate control (e.g., Müller et al. 2006).An alternative to variable selection with mixture priors is classical and Bayesian shrinkage- or penalty-based inference. For the classical approach of penalized regression, while an L₂-based shrinkage method (ridge regression) cannot perform variable selection, other methods, in particular the L₁-based lasso of Tibshirani (1996) and later lasso extensions, are capable of performing variable selection by reducing the effects of unimportant variables effectively to zero. The lasso has been applied to parametric, regression-based QTL mapping (Yi and Xu 2008). The penalized regression methods can be interpreted as Bayesian regression models with particular sparsity priors imposed on the regression coefficients (Park and Casella 2008).Regression methods are also used for association mapping in human populations. Recently, Kwee et al. (2008) proposed a semiparametric regression-based approach for candidate regions in human association mapping, where a quantitative trait is regressed on a nonparametric function of the tagSNP genotypes within a region. They analyzed a (small) subset of the genome and tested for the joint significance of the subset. Their method potentially can be used to model interactions among SNPs and covariates. However, Kwee et al. (2008) fit their model using least-squares kernel machines, a dimension-reducing technique that is identical to an analysis based on a specific linear mixed model. Model selection for different types of kernels and different sets of variables is performed using criteria such as Akaike''s information criteria (Akaike 1974) and Bayesian information criteria (Schwarz 1978), which may not be appropriate or feasible in large-scale, sparse variable selection situations.We (Huang et al. 2010) recently developed a Bayesian semiparametric QTL mapping method, where nongenetic covariate effects are modeled nonparametrically. This method was implemented via MCMC, and a Gaussian process prior (O''Hagan 1978; Neal 1996, 1997) was placed on the unknown covariate function. The Gaussian process is particularly well suited for curve estimation due to its flexible sample path shapes. This method allows one or more nongenetic covariates to have an arbitrary (nonlinear) relationship with the phenotype. Another strong advantage of the Gaussian process is its ability to deal with high-dimensional data compared to other nonparametric techniques such as spline regression (Wahba 1984; Heckman 1986; Chen 1988; Speckman 1988; Cuzick 1992; Hastie and Loader 1993). There has been a growing interest in using Gaussian processes as a unifying framework for studying multivariate regression (Rasmussen 1996), pattern classification (Williams and Barber 1998), and hierarchical modeling (Menzefricke 2000). In this article, we build on this work and propose a nonparametric Bayesian method for multiple QTL mapping by including not only nongenetic covariates but also all candidate QTL in the unknown function. A Gaussian process prior (GPP) is again placed on the unknown function, and a variable selection approach is implemented for the hyperparameters of the GPP (one for each QTL and nongenetic covariate). Here, we rely on mixture priors and MCMC implementation, and we focus on linkage mapping in inbred line crosses, while in ongoing and future work we are considering shrinkage priors, deterministic algorithms, and association mapping. Our application of the GPP differs from “standard” applications in that the QTL covariates included in the unknown function are discrete, not continuous, with a small number (two or three) of possible values (the genotype codes). The goal of using a GPP here is not curve or response surface modeling but rather high-dimensional variable selection (QTL and nongenetic covariates) with a method requiring only a single parameter for each variable while accounting for any multiway interactions among the candidate variables.To improve current methods for linkage mapping in inbred line crosses and for association analysis of human populations, we need to be able to detect QTL irrespective of whether they act mostly through main effects, interactions with other QTL, or interactions with environment. Fitting a parametric model including all these potential effects for a genome-wide search would substantially increase the multiple-testing problem, in addition to being computationally extremely demanding. Here we offer an alternative. We show that our nonparametric Bayesian method can identify QTL irrespective of whether they act through main effects, through interactions with other QTL, or with environmental factors. This method cannot identify the source(s) of a QTL''s importance (main or interaction effects involving this QTL). Therefore, once a small number of important QTL have been identified in a genome-wide scan, then these QTL can be further analyzed with detailed parametric models to determine the source(s) of their importance.The remainder of the article is organized as follows. We first present the nonparametric multiple-QTL model and outline the MCMC sampler in the next section. Simulation results and the analysis of a real data set are presented in the section following that. And we end the article with a discussion and conclusions.     

Seed development: With or without sex?

In Arabidopsis, mutations in the genes FIE, FIS2 or MEDEA disrupt the normal dependence of seed development on fertilization. The products of these genes are similar to Polycomb group proteins, suggesting possible mechanisms for determining whether seeds can be produced sexually or asexually.     

Factors Associated With Shift Work Disorder in Nurses Working With Rapid-Rotation Schedules in Japan: The Nurses’ Sleep Health Project

Workers who meet the criteria for shift work disorder (SWD) have elevated levels of risk for various health and behavioral problems. However, the impact of having SWD on shiftworkers engaged in rapid-rotation schedules is unknown. Moreover, the risk factors for the occurrence of SWD remain unclear. To clarify these issues, we conducted a questionnaire-based, cross-sectional survey on a sample of shiftworking nurses. Responses were obtained from 1202 nurses working at university hospitals in Tokyo, Japan, including 727 two-shift workers and 315 three-shift workers. The questionnaire included items relevant to age, gender, family structure, work environment, health-related quality of life (QOL), diurnal type, depressive symptoms, and SWD. Participants who reported insomnia and/or excessive sleepiness for at least 1 mo that was subjectively relevant to their shiftwork schedules were categorized as having SWD. The prevalence of SWD in the sampled shiftworking nurses was 24.4%; shiftworking nurses with SWD showed lower health-related QOL and more severe depressive symptoms, with greater rates of both actual accidents/errors and near misses, than those without SWD. The results of logistic regression analyses showed that more time spent working at night, frequent missing of nap opportunities during night work, and having an eveningness-oriented chronotype were significantly associated with SWD. The present study indicated that SWD might be associated with reduced health-related QOL and decreased work performance in shiftworking nurses on rapid-rotation schedules. The results also suggested that missing napping opportunities during night work, long nighttime working hours, and the delay of circadian rhythms are associated with the occurrence of SWD among shiftworking nurses on rapid-rotation schedules. (Author correspondence: yuinoue@tokyo-med.ac.jp)     

NONCICATRIZING ALOPECIAS—With Special Reference to Alopecia Areata

Since the epochal work of Hamilton there has been general acceptance of the causal relationship of the male sex hormone, age and familial inheritance in development of male pattern baldness.Some of the medicaments used in recent years may cause a diffuse loss of scalp hair. Alopecia that accompanies disease states is probably due to generalized toxemia and disturbances in metabolism. Sometimes male pattern baldness occurs in physiologic states, as exemplified by diffuse hair loss occasionally in the postpartum period.Alopecia areata deserves a critical appraisal, since it may be evidence of underlying neuropsychotic states that need psychiatric diagnosis and treatment. The development of alopecia totalis or universalis in 50 per cent of the prepuberal cases of alopecia areata is of real significance, especially since so very few patients recover their normal scalp hair.The conclusions reached by the authors of two articles reporting on 368 cases of alopecia areata, alopecia totalis and alopecia universalis that the evidence is overwhelming against the malfunction of the endocrine glands as the cause of alopecia areata must be considered real contributions to our understanding of this condition.A few conditions simulate alopecia areata. Probably the ones which are seen most often are trichotillomania and patchy baldness caused by agents used in hair waving and straightening.Our findings in 22 cases of alopecia areata of a persistent inflammatory perivascular and perifollicular infiltrate, massive plugging of the ostia, disappearance of robust hair follicles and diminution in total number of hair follicles and sometimes fibrosis are not necessarily diagnostic of alopecia areata but seem to be very definitely characteristic.Treatment for alopecia areata is of little avail. At this time we do not recommend the general use of the corticosteroids despite the improvement of scalp appearance in the majority of instances in which the systemic administration of these hormones have been employed.     

Νον-Islet Cell Tumor Hypoglycemia Associated With Uterine Leiomyomata

ObjectiveWe report a case of non-islet cell tumor hypoglycemia (NICTH) in a patient with large leiomyomata.MethodsWe present the clinical, laboratory, and pathologic findings of a diabetic patient who presented with recurrent hypoglycemia later linked to uterine leiomyomata.ResultsAn 80-year-old woman with diabetes was admitted after falling at home. She reported dizziness and had recorded low capillary blood glucose despite discontinuing her diabetic medication prior to admission. Her physical examination was remarkable for nonorthostatic vital signs, normal cardiovascular and lung examination, and a pelvi-abdominal mass the size of a gravid uterus at 28 weeks of gestation. After receiving a 50% dextrose infusion, she became alert with no focal neurological deficit. Capillary blood glucose rose from 31 mg/ dL to 110 mg/dL. A pelvic sonogram confirmed fibromyomata. She was initially treated with steroids after ahormonal profile suggested NICTH (normal fasting insulin, C-peptide, cosyntropin and glucagon stimulation tests, and negative insulin antibodies). Insulinlike growth factor (IGF) levels were IGF-1, 69 ng/mL and IGF-2, 782 ng/mL, and the IGF-2/IGF-1 ratio was 10.8. The patient underwent a total abdominal hysterectomy. Pathology reported a 3-kg uterus with multiple, large cellular fibromyomas. After steroids were discontinued, she became hyperglycemic requiring insulin and oral diabetic agents. Repeat IGF-2 and IGF-1 measurements were 261 ng/mL and 36 ng/mL, respectively. She was discharged 2 weeks after surgery.ConclusionNICTH is a rare complication associated with large neoplasms. Leiomyomata should be included in the differential diagnoses of NICTH. Surgery is curative in such cases. (Endocr Pract. 2011;17:e109-e112)     

Studying Herpesvirus Pathogenesis Using SCID Mice Implanted With Human Tissues

Human cytomegalovirus(HCMV)and Varicella Zoster virus(VZV)are belongto herpesvirusfamily.HCMVrarelycaus-es symptomatic diseaseinanimmunocompetent host;however,itis a major cause of infectious morbidityand mortalityinimmunocompromised individuals and developingfetuses.VZVinfectioncauses chickenpoxandshingles.Sincethese spe-cies-specific herpesviruses do notinfect other animals,noanimal model is availablefor pathogenesis studies.Severe com-binedimmunodeficient(SCID)mice implanted with hu…     

Adrenal Cortical Carcinoma With Late Pulmonary Metastases Causing Clinicical Cushing’s Syndrome: Case Report With Immunohistochemical Analysis Of Steriodogenic Enzyme Production

ObjectiveTo present a case of pulmonary metastases from adrenocortical carcinomas (ACC) that were secreting fully-functional cortisol resulting in clinical Cushing’s syndrome and to compare the steroidogenic enzyme expression in the primary tumor and lung.MethodsWe analyzed and summarized the patient’s medical history, physical examination results, labora tory data, imaging studies, and histopathologic results. The original tumor and the pulmonary metastases were then immunohistochemically evaluated for steroidogenic enzymes.ResultsInitial endocrinological workup revealed hyperandrogenism and adrenocorticotropic hormone (ACTH) independent Cushing’s due to a 4 cm left adrenal mass. The patient was initially diagnosed with an adrenal adenoma. Four years later, the patient developed recurrent Cushing’s syndrome. Repeat magnetic resonance imaging (MRI) showed no adrenal masses; however, chest computed tomography (CT) showed multiple bilateral lung nodules and biopsy revealed metastases of adrenal origin. Upon immunohistochemical analysis, side chain cleavage, 17α hydroxylase, 3β hydroxysteroid dehydrogenase, and 21 hydroxylase immunoreactivity were detected in both the original and pulmonary metastatic lesions with patterns of disorganized steroidogenesis. Dehydroepiandrosterone sulfotransferase (DHEA-ST) immunoreactivity was detected in the original tumor but not in the lung metastases.ConclusionThis case demonstrates some inter esting features of ACC that pose challenges to its management, including the difficulties in establishing the pathologic diagnosis, the potential for fullyfunctional steroidogenesis even in late metastases, and the plasticity of steroidogenic potential in tumor cells. (Endocr Pract. 2012;18:e138-e143)     

Nucleocytoplasmic trafficking of proteins: With or without Ran?

Proteins and RNAs move between the nucleus and cytoplasm by translocation through nuclear pore complexes in the nuclear envelope. To do this, they require specific targeting signals, energy, and a cellular apparatus that catalyzes their transport. Several of the factors involved in nucleocytoplasmic trafficking of proteins have been identified and characterized in some detail. The emerging picture for nuclear transport proposes a central role for the small GTPase Ran and proteins with which it interacts. In particular, asymmetric distribution of these proteins between nucleus and cytoplasm appears to be responsible for the vectorial nature of nucleocytoplasmic transport. Here, we summarize the role of Ran and Ran-binding proteins in nuclear trafficking of proteins with classical nuclear localisation signals. We also discuss examples of the growing number of alternative pathways that are involved in transport of proteins across the nuclear envelope. BioEssays 21:579–589, 1999. © 1999 John Wiley & Sons, Inc.     

Fluorescent antibody method Conjugation Of Fluoresceinisothiocyanate With Immune ?-Globulin

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With the finished human genome in hand,what next?

A report on the eighth annual meeting of the Human Genome Organization (HGM2003), Cancun, Mexico, 27-30 April 2003.     

Is Psychiatric Illness Associated With Worse Outcomes Following Pilon Fracture?

BackgroundPatients with psychiatric comorbidities represent a significant subset of those sustaining pilon fractures. The purpose of this study is to examine the association of psychiatric comorbidities (PC) in patients with pilon fractures and clinical outcomes.MethodsA multi-institution, retrospective review was conducted. Inclusion/exclusion criteria were skeletally mature patients with a tibia pilon fracture (OTA Type 43B/C) who underwent definitive fracture fixation utilizing open reduction internal fixation (ORIF) with a minimum of 24 weeks of follow-up. Patients were stratified into two groups for comparison: PC group and no PC group.ResultsThere were 103 patients with pilon fractures that met the inclusion/exclusion criteria of this study. Of these patients, 22 (21.4%) had at least one psychiatric comorbidity (PC) and 81 (78.6%) did not have psychiatric comorbidities (no PC). There was a higher percentage of female patients (PC: 59.1% vs no PC: 25.9%, p=0.0.005), smokers (PC: 40.9% vs no PC: 16.0%, p=0.02), and drug users (PC: 22.7% vs no PC: 8.6%, p=0.08) amongst PC patients. Fracture comminution (PC: 54.5% vs no PC: 32.1%, p=0.05) occurred more frequently in PC patients. The PC group had a higher incidence of weightbearing noncompliance (22.7% vs 7.5%, p=0.04) and reoperation (PC: 54.5% vs no PC: 29.6%, p=0.03).ConclusionPatients with psychiatric comorbidities represent a significant percentage of pilon fracture patients and appear to be at higher risk for postoperative complication. Risk factors that may predispose patients in the PC group include smoking/substance use, weightbearing noncompliance, and fracture comminution. Level of Evidence: III     

RIGHT DIAPHRAGMATIC HERNIA SECONDARY TO TRAUMA—With Report of Two Cases

With automobile accidents at high speed on the increase, some previously rare injuries are becoming more common. Rupture of the left diaphragm is fairly common. On the right, it has been believed rare. The diagnosis has often been missed for many years after the causative injury.Any suspicious x-ray film shadow at the base of the right lung field after injury such as those that occur in accidents of great impact should arouse the physician''s suspicions. A mushroom-shaped mass on the lateral x-ray view is characteristic.Introduction of pneumoperitoneum may help in diagnosis. Only if the peritoneal and pleural cavities communicate will this procedure produce a pneumothorax.Surgical correction is indicated in all cases. This is best done through the chest. The right lobe of the liver usually must be reduced. In general the results are excellent.     

Subspecialty Differences in Responding to Patient Death–Comparing Cardiologists With Oncologists

Cardiac deaths are more likely to be unanticipated than cancer deaths by patients, their families, and their physicians. We hypothesized that differing physician attitudes toward dying patients may affect the degree of expectation of death. To evaluate differences in attitudes and behaviors among subspecialists, we surveyed a randomly selected population of California subspecialists; 44 of 136 (32%) of cardiologists and 91 of 167 (55%) of oncologists responded. Oncologists experienced three times as many deaths as cardiologists and reported having discussed code status more often with patients who died. Cardiologists'' patients'' deaths were more often unexpected and occurred more frequently in intensive care units. In addition, their patients were more likely to be given cardiopulmonary resuscitation. Oncologists reported being more comfortable dealing with dying patients and having less desire to avoid them. When presented with patient scenarios, however, cardiologists'' and oncologists'' responses were similar when discussing and estimating prognosis and likelihood of successful therapy.