Distinct Disease States Research Articles

Abstract 2792: Polymorphisms in vitamin D-related genes and risk of breast cancer

Abstract Vitamin D is hypothesized to decrease breast cancer risk by controlling cell proliferation, differentiation and apoptosis, and estrogen synthesis and signalling in breast tissue. Transport of circulating vitamin D to sites of action is facilitated by vitamin D binding protein, encoded by the GC gene, whereupon it binds to the vitamin D receptor, encoded by the VDR gene. Given that polymorphisms in the GC and VDR gene have not been consistently associated with breast cancer risk, our objective was to assess the associations of vitamin D-related genes with breast cancer risk, accounting for ethnicity and menopausal status, and to determine these associations according to tumour receptor status defined by expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2). A case-control study of 1,037 breast cancer cases and 1,050 controls age-frequency matched in Vancouver, British Columbia and Kingston, Ontario was used. The distribution and associations of 21 single nucleotide polymorphisms (SNPs) of the GC and VDR gene with breast cancer risk and breast tumour subtypes were investigated among premenopausal and postmenopausal European and Asian women in stratified analyses. Following false discovery rate adjustment, no SNP was associated with breast cancer risk among any subgroup. However, among European women, two SNPs in the VDR gene, rs1544410 (OR = 0.38, 95% CI: 0.21 - 0.70) and rs7967152 (OR = 2.80, 95% CI: 1.62 - 4.85) were associated with risk of ER-/PR-/HER2+ breast tumour subtype, but not with other breast tumour subtypes. Breast tumour subtypes are proposed to be etiologically distinct disease states, with different risk factors and prognostic outcomes. Interactions between variations in vitamin D-related genes and breast tumour subtypes are biologically plausible given our current understanding of anticarcinogenic properties of vitamin D elicited through the regulation of cell growth and reproductive hormone synthesis. These findings provide additional insight into the etiologic differences among breast tumour subtypes. Citation Format: Joy Shi, Anne Grundy, Harriet Richardson, Angela Brooks-Wilson, John Spinelli, Kristan J. Aronson. Polymorphisms in vitamin D-related genes and risk of breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2792. doi:10.1158/1538-7445.AM2015-2792

Small molecule and RNAi induced phenotype transition of expanded and primary colonic epithelial cells.

Recent progress in mammalian intestinal epithelial cell culture led to novel concepts of tissue modeling. Especially the development of phenotypically stable cell lines from individual animals enables an investigation of distinct intestinal loci and disease states. We here report primary and prolonged culture of normal porcine epithelial cells from colon for cell line development. In addition, a novel primary three-dimensional intestinal culture system is presented, which generated organoids composed of a highly polarized epithelial layer lining a core of subepithelial tissue. Cellular characterization of monolayer cell lines revealed epithelial identity and pointed to a proliferative crypt cell phenotype. We evaluated both RNAi and chemical approaches to induce epithelial differentiation in generated cell lines by targeting promoters of epithelial to mesenchymal transition (EMT). By in silico prediction and ectopic expression, miR-147b was proven to be a potent trigger of intestinal epithelial cell differentiation. Our results outline an approach to generate phenotypically stable cell lines expanded from primary colonic epithelial cultures and demonstrate the relevance of miR-147b and chemical inhibitors for promoting epithelial differentiation features.

Multivariate inference of pathway activity in host immunity and response to therapeutics

Developing a quantitative view of how biological pathways are regulated in response to environmental factors is central for understanding of disease phenotypes. We present a computational framework, named Multivariate Inference of Pathway Activity (MIPA), which quantifies degree of activity induced in a biological pathway by computing five distinct measures from transcriptomic profiles of its member genes. Statistical significance of inferred activity is examined using multiple independent self-contained tests followed by a competitive analysis. The method incorporates a new algorithm to identify a subset of genes that may regulate the extent of activity induced in a pathway. We present an in-depth evaluation of specificity, robustness, and reproducibility of our method. We benchmarked MIPA's false positive rate at less than 1%. Using transcriptomic profiles representing distinct physiological and disease states, we illustrate applicability of our method in (i) identifying gene–gene interactions in autophagy-dependent response to Salmonella infection, (ii) uncovering gene–environment interactions in host response to bacterial and viral pathogens and (iii) identifying driver genes and processes that contribute to wound healing and response to anti-TNFα therapy. We provide relevant experimental validation that corroborates the accuracy and advantage of our method.

Coral transcriptome and bacterial community profiles reveal distinct Yellow Band Disease states in Orbicella faveolata.

Coral diseases impact reefs globally. Although we continue to describe diseases, little is known about the etiology or progression of even the most common cases. To examine a spectrum of coral health and determine factors of disease progression we examined Orbicella faveolata exhibiting signs of Yellow Band Disease (YBD), a widespread condition in the Caribbean. We used a novel combined approach to assess three members of the coral holobiont: the coral-host, associated Symbiodinium algae, and bacteria. We profiled three conditions: (1) healthy-appearing colonies (HH), (2) healthy-appearing tissue on diseased colonies (HD), and (3) diseased lesion (DD). Restriction fragment length polymorphism analysis revealed health state-specific diversity in Symbiodinium clade associations. 16S ribosomal RNA gene microarrays (PhyloChips) and O. faveolata complimentary DNA microarrays revealed the bacterial community structure and host transcriptional response, respectively. A distinct bacterial community structure marked each health state. Diseased samples were associated with two to three times more bacterial diversity. HD samples had the highest bacterial richness, which included components associated with HH and DD, as well as additional unique families. The host transcriptome under YBD revealed a reduced cellular expression of defense- and metabolism-related processes, while the neighboring HD condition exhibited an intermediate expression profile. Although HD tissue appeared visibly healthy, the microbial communities and gene expression profiles were distinct. HD should be regarded as an additional (intermediate) state of disease, which is important for understanding the progression of YBD.

Towards the determination of isoprene in human breath using substrate-integrated hollow waveguide mid-infrared sensors

Selected volatile organic compounds (VOCs) in breath may be considered biomarkers if they are indicative of distinct diseases or disease states. Given the inherent molecular selectivity of vibrational spectroscopy, infrared sensing technologies appear ideally suitable for the determination of endogenous VOCs in breath. The aim of this study was to determine that mid-infrared (MIR; 3–20 µm) gas phase sensing is capable of determining isoprene in exhaled breath as an exemplary medically relevant VOC by hyphenating novel substrate-integrated hollow waveguides (iHWG) with a likewise miniaturized preconcentration system. A compact preconcentrator column for sampling isoprene from exhaled breath was coupled to an iHWG serving simultaneously as highly miniaturized gas cell and light conduit in combination with a compact Fourier transform infrared spectrometer. A gas mixing system enabled extensive system calibration using isoprene standards. After system optimization, a calibration function obtaining a limit of quantification of 106 ppb was achieved. According to the literature, the obtained sensitivity is sufficient for quantifying middle to high isoprene concentrations occurring in exhaled breath. Finally, a volunteer breath sample was analysed proving comparable values of isoprene in a real-world scenario. Despite its fundamental utility, the proposed methodology contains some limitations in terms of sensitivity and temporal resolution in comparison with the readily available measurement techniques that should be addressed during future optimization of the system. Nonetheless, this study presents the first determination of endogenous VOCs in breath via advanced hollow waveguide MIR sensor technology, clearly demonstrating its potential for the analysis of volatile biomarkers in exhaled breath.

Causal inference of gene regulation with subnetwork assembly from genetical genomics data

Deciphering the causal networks of gene interactions is critical for identifying disease pathways and disease-causing genes. We introduce a method to reconstruct causal networks based on exploring phenotype-specific modules in the human interactome and including the expression quantitative trait loci (eQTLs) that underlie the joint expression variation of each module. Closely associated eQTLs help anchor the orientation of the network. To overcome the inherent computational complexity of causal network reconstruction, we first deduce the local causality of individual subnetworks using the selected eQTLs and module transcripts. These subnetworks are then integrated to infer a global causal network using a random-field ranking method, which was motivated by animal sociology. We demonstrate how effectively the inferred causality restores the regulatory structure of the networks that mediate lymph node metastasis in oral cancer. Network rewiring clearly characterizes the dynamic regulatory systems of distinct disease states. This study is the first to associate an RXRB-causal network with increased risks of nodal metastasis, tumor relapse, distant metastases and poor survival for oral cancer. Thus, identifying crucial upstream drivers of a signal cascade can facilitate the discovery of potential biomarkers and effective therapeutic targets.

Mental disorders as “brain diseases” and Jaspers’ legacy

Mental disorders as “brain diseases” and Jaspers’ legacy

Novel Integrative Genomics Approach for Associating GWAS Information with Intrinsic Subtypes of Breast Cancer

Genome-wide association studies (GWAS) have achieved great success in identifying common variants associated with increased risk of developing breast cancer. However, GWAS do not typically provide information about the broader context in which genetic variants operate in different subtypes of breast cancer. The objective of this study was to determine whether genes containing single nucleotide polymorphisms (SNPs, herein called genetic variants) are associated with different subtypes of breast cancer. Additionally, we sought to identify gene regulator networks and biological pathways enriched for these genetic variants. Using supervised analysis, we identified 201 genes that were significantly associated with the six intrinsic subtypes of breast cancer. The results demonstrate that integrative genomics analysis is a powerful approach for linking GWAS information to distinct disease states and provide insights about the broader context in which genetic variants operate in different subtypes of breast cancer.

Local hematopoietic renin-angiotensin system in myeloid versus lymphoid hematological neoplastic disorders

There is preliminary evidence that the local renin-angiotensin system (RAS) could affect neoplastic hematopoiesis. The aim of this study is to search messenger RNA (mRNA) expressions of the essential RAS elements in myeloid and lymphoid hematological neoplastic disorders. Forty-six patients with newly diagnosed myeloid (AML, biphenotypic leukemia, CML) or lymphoid (CLL, NHL, B-ALL, T-ALL) hematological disorders were included in the study. In the lymphoid group, the median expression values of RENIN, ACE1, ACE2 and ANGIOTENSINOGEN (ANGTS) mRNAs were 1.96%, 0.42%, 0.00% and 0.00%, respectively; in the myeloid group, 0.73%, 1.55%, 0.04% and 0.006%, respectively. In the lymphoid group, RENIN levels were significantly higher (p = 0.001), whereas ACE1 and ACE2 levels were significantly higher in the myeloid group (p values were 0.013 and 0.010, respectively). ANGTS levels were similar in both groups. In patients with non-ALL lymphoid malignancies, RENIN expressions were significantly higher when compared to ALL patients (p = 0.004). All patients with active disease had significantly higher RENIN mRNA expression levels than patients without active disease (2.03% vs 0.30%) (p = 0.034). The result of our present study indicates that the activities of local RAS may differ in distinct disease states such as leukemia and lymphomas.

Pericardial Diseases

The pericardium provides an enclosed lubricated space for the beating heart and functions to fix the heart in the chest cavity relative to adjacent organs. Pericardial pathophysiology is often manifested in a spectrum of distinct cardiac and systemic disease states. The pericardial response to injury typically involves a spectrum of inflammation with both acute and chronic features and/or fluid accumulation. Recent advances in imaging methods have refined the diagnosis and therapy of pericardial disease. This article presents the anatomy and physiology of pericardial disease and the clinical approach for diagnosis and treatment.

Ask the Expert: Bipolar Disorder

Back to table of contents Previous article Next article CLINICAL SYNTHESISFull AccessAsk the Expert: Bipolar DisorderMark A. Frye, M.D.Mark A. FryeSearch for more papers by this author, M.D.Published Online:1 Oct 2011https://doi.org/10.1176/foc.9.4.foc455AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail In meetings and presentations, I am increasingly hearing the term “mixed depression”—what is it and how best should I be treating it?There is no consensus or operationalized criteria for mixed depression. There are however, several definitions that generally define the concept as a syndromal episode of major depression plus several symptoms (i.e., nonsyndromal) of mania/hypomania (1–4). Review, for example, the following case report.A 30-year-old businesswoman sought consultation for persistent depressive symptoms and increased irritability despite ongoing antidepressant (venlafaxine 300 mg) and mood stabilization (divalproex sodium 1000 mg) cotherapy. She had been treated with divalproex since her first and only admission 10 years ago for nonpsychotic mixed mania complicated by alcohol abuse and migraine. Her current symptoms include depressed mood, anhedonia, guilty ruminations, early morning awakening with reduced appetite, and weight loss. In addition, she reports irritability, racing thoughts, distractibility, and an uncomfortable energy that she describes as “pushed, hyperactive, wired and tired.” All these symptoms were present despite a therapeutic level of valproate (60 mcg/dl). The addition of venlafaxine has reduced the symptom severity of depression and anhedonia by 50% but the irritability, racing thoughts, and agitation have increased.This presentation (i.e., episode of major depression with concurrent minimal hypomanic symptoms and a history of mania) is consistent with mixed depression. It is increasingly recognized that mixed depression is not uncommon as more than 50% of depressed patients with bipolar disorder followed in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) program study reported subsyndromal symptoms of mania/hypomania; most commonly, the symptoms were distractibility, racing thought/flight of ideas, increased activity, and increased speech (5).This distinction between mixed depression and traditional or DSM-IV-TR mixed mania [major depression plus three manic (euphoric)/or four (mixed) symptoms)] or mixed hypomania (6) is unclear. It is unlikely that one symptom would distinguish distinct categorical disease states. More likely is a spectrum of mixed presentations with original Kraepelinian descriptions (i.e., depressive or anxious mania, excited depression, and depression with flight of ideas) that remain timelessly rich (7). It is clear that DSM-5 is focusing on this categorical versus dimensional aspect of mixed presentations in mood disorder (8). The proposed revision is to have a “mixed features specifier,” which would apply “in episodes where subthreshold symptoms from the opposing pole are present during a full mood episode”; these symptoms may be “relatively simultaneous,” or “they may also occur closely juxtaposed in time as a waxing and waning of individual symptoms of the opposite pole.”What remains is how best to treat mixed depression. There are few data other than studies that show, in comparison to nonmixed depression, reduced response to antidepressant therapy and antidepressant-induced mania (9, 10). A recent 6-week randomized, double-blind, placebo-controlled study, which reported efficacy of ziprasidone in mixed depression (n = 44 bipolar II and 30 major depressive disorder), is the first study to look at mood stabilization therapy (11). Further study for diagnostic clarification in bipolar and unipolar disorders as well as treatment guidelines is warranted.Author Information and CME DisclosureMark A. Frye, M.D., Professor & Chair, Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN.Grant Support: Pfizer, National Alliance for Schizophrenia and Depression (NARSAD), NIMH, NIAAA, Mayo Foundation

Pharmacoperones: A New Therapeutic Approach for Diseases Caused By Misfolded G Protein-Coupled Receptors

G Protein-coupled receptors (GPCRs) are cell membrane proteins that recognize specific chemical signals such as drugs and hormones and transduce these signals into cellular responses by activating G-proteins. As is the case for all newly synthesized proteins, GPCRs are subjected to conformational scrutiny at the endoplasmic reticulum prior to processing and trafficking to the cell surface membrane. Because of this stringent quality control screening mechanism, mutations that result in protein misfolding frequently lead to retention in the endoplasmic reticulum, aggregation or other misrouting and, eventually, to disease. This article reviews some patents and new therapeutic opportunities based on the misfolding and retention of otherwise functional GPCRs that represent promising approaches to correct conformational abnormalities leading to distinct disease states.

A synergistic small-molecule combination directly eradicates diverse prion strain structures

Safely eradicating prions, amyloids and preamyloid oligomers may ameliorate several fatal neurodegenerative disorders. Yet, whether small-molecule drugs can directly antagonize the entire spectrum of distinct amyloid structures or ‘strains’ that underlie distinct disease states is unclear. Here, we investigated this issue using the yeast prion protein Sup35. We have established how epigallocatechin-3-gallate (EGCG) blocks synthetic Sup35 prionogenesis, eliminates preformed Sup35 prions, and disrupts inter- and intra-molecular prion contacts. Unexpectedly, these direct activities were strain selective, altered the repertoire of accessible infectious forms and facilitated emergence of a new prion strain that configured original, EGCG-resistant intermolecular contacts. In vivo, EGCG cured and prevented induction of susceptible but not resistant strains, and elicited switching from susceptible to resistant forms. Importantly, 4,5-bis-(4-methoxyanilino)phthalimide directly antagonized EGCG-resistant prions and synergized with EGCG to eliminate diverse Sup35 prion strains. Thus, synergistic small-molecule combinations that directly eradicate complete strain repertoires likely hold considerable therapeutic potential.

The meaning of clinical remission in polyarticular juvenile idiopathic arthritis: gene expression profiling in peripheral blood mononuclear cells identifies distinct disease states.

The development of biomarkers to predict response to therapy in polyarticular juvenile idiopathic arthritis (JIA) is an important issue in pediatric rheumatology. A critical step in this process is determining whether there is biologic meaning to clinically derived terms such as "active disease" and "remission." The aim of this study was to use a systems biology approach to address this question. We performed gene transcriptional profiling on children who fulfilled the criteria for specific disease states as defined by the consensus criteria developed by Wallace and colleagues. The study group comprised children with active disease (n = 14), children with clinical remission on medication (CRM; n = 9), children with clinical remission off medication (CR; n = 6), and healthy control children (n = 13). Transcriptional profiles in peripheral blood mononuclear cells (PBMCs) were obtained using Affymetrix U133 Plus 2.0 arrays. Hierarchical cluster analysis and predictive modeling demonstrated that the clinically derived criteria represent biologically distinct states. Minimal differences were seen between children with active disease and those with disease in CRM. Thus, underlying immune/inflammatory abnormalities persist despite a response to therapy. The PBMC transcriptional profiles of children whose disease was in remission did not return to normal but revealed networks of proinflammatory and antiinflammatory genes, suggesting that remission is a state of homeostasis, not a return to a normal state. Gene transcriptional profiling of PBMCs revealed that clinically derived criteria for JIA disease states reflect underlying biology. We also demonstrated that neither CRM nor CR status results in resolution of the underlying inflammatory process, but that these conditions are more likely to be states of balanced homeostasis between proinflammatory and antiinflammatory mechanisms.

Soluble Platelet Glycoprotein V in Distinct Disease States of Pathological Thrombopoiesis

Quantitative platelet disorders (i.e., thrombocytosis or thrombocytopenia) may also be associated with qualitative platelet alterations. Clonal thrombocythemia (CT), reactive thrombocytosis (RT), immune thrombocytopenic purpura (ITP), and thrombocytopenia of aplastic pancytopenia (AA) or infiltrative bone marrow disorders represent the major classes of pathological thrombopoiesis. Glycoprotein V may serve as an in vivo marker of platelet activation in thrombotic and hemorrhagic states. The aim of this study was to assess circulating plasma soluble platelet glycoprotein V (sGPV) concentrations in distinct disease states of pathological thrombopoiesis. The whole study group comprised 20 patients with thrombocytopenia, 32 patients with thrombocytosis and 14 healthy adults as the control group. sGPV was significantly increased in the group of thrombocytosis patients in comparison to the thrombocytopenic group and the healthy control groups. When sGPV levels were corrected according to platelet number (sGPV/tr), this ratio was very high in patients with thrombocytopenia compared to patients with thrombocytosis and the control group. Our results suggest that there is an ongoing platelet activation associated with thrombocytosis regardless of its origin is either CT or RT. Therefore, glycoprotein V system may serve to activate residual platelets in thrombocytopenia regardless of its origin is either ITP or AA.

Impact of Admission Hyperglycemia and Diabetes Mellitus on Short- and Long-Term Mortality After Acute Myocardial Infarction in the Coronary Intervention Era

The influence of admission hyperglycemia and diabetes on short- and long-term mortality of patients with acute myocardial infarction (AMI) in the percutaneous coronary intervention (PCI) era was investigated. From 1996 to 2003, a total of 802 consecutive patients with AMI underwent coronary angiography. Primary PCI was performed in 724 patients (90%). Three-year mortality curves were constructed using the Kaplan-Meier method. Cox proportional hazard regression was used to identify independent predictors of 30-day mortality and mortality from 30 days to 3 years. There were 261 patients with admission hyperglycemia (admission glucose>or=11.1 mmol/L) and 212 patients with diabetes. Admission hyperglycemia was associated with a significantly higher 30-day mortality rate (8.4% vs 2.4%, p<0.001). However, there was no significant difference in 30-day mortality rates between diabetic and nondiabetic patients (5.7% vs 3.9%, p=0.29). Conversely, diabetes significantly increased mortality from 30 days to 3 years (10.0% vs 5.5%, p=0.03), but admission hyperglycemia did not (8.4% vs 5.9%, p=0.19). Multivariate analysis showed that hyperglycemia was an independent predictor of 30-day mortality (odds ratio [OR] 1.71, 95% confidence interval [CI] 1.13 to 2.61, p=0.01), but diabetes was not (OR 0.84, 95% CI 0.55 to 1.27, p=0.42). Diabetes was independently associated with mortality from 30 days to 3 years (OR 1.43, 95% CI 1.02 to 1.97, p=0.04), but hyperglycemia had a neutral effect (OR 0.98, 95% CI 0.70 to 1.36, p=0.92). In conclusion, in the PCI era, admission hyperglycemia was associated with short-term mortality, whereas diabetes increased long-term mortality after convalescence in patients with AMI. Admission hyperglycemia and diabetes should be treated as 2 distinct disease states.

Predicting Chronic Leukaemias from Assessment of Complete Peripheral Blood Counts

The chronic leukaemias include two distinct chronic neoplastic disease states, namely chronic myelogenous leukaemia (CML) and chronic lymphocytic leukaemia (CLL). The aim of this study was to assess the utility of leucocyte count, neutrophil percentage and absolute lymphocyte count from differential complete blood count analyses as indicators of the possible presence of CML and CLL. Blood counts from 102 patients with histopathologically confirmed CML and CLL were compared with counts for 858 cancer-free control subjects. Optimal cut-off values were identified by selecting values with the highest sensitivity-specificity combination for each blood count parameter for the two diseases. The results indicated that any individual with mature-appearing lymphocytes at a level > 6.65 x 10(9)/l in the peripheral blood should be examined further for CLL, and that any individual with a leucocyte count > 18.0 x 10(9)/l or a neutrophil proportion > 72.6% should be investigated for CML.

Molecular mechanisms of mitochondrial diabetes (MIDD)

Mitochondria provide cells with most of the energy in the form of adenosine triphosphate (ATP). Mitochondria are complex organelles encoded both by nuclear and mtDNA. Only a few mitochondrial components are encoded by mtDNA, most of the mt‐proteins are nuclear DNA encoded. Remarkably, the majority of the known mutations leading to a mitochondrial disease have been identified in mtDNA rather than in nuclear DNA. In general, the idea is that these pathogenic mutations in mtDNA affect energy supply leading to a disease state. Remarkably, different mtDNA mutations can associate with distinct disease states, a situation that is difficult to reconcile with the idea that a reduced ATP production is the sole pathogenic factor. This review deals with emerging insight into the mechanism by which the A3243G mutation in the mitochondrial tRNA (Leu, UUR) gene associates with diabetes as major clinical expression. A decrease in glucose‐induced insulin secretion by pancreatic beta‐cells and a premature aging of these cells seem to be the main process by which this mutation causes diabetes. The underlying mechanisms and variability in clinical presentation are discussed.

Endogenous thrombopoietin levels during the clinical management of acute myeloid leukaemia

Thrombocytopenia represents a major problem in the management of acute myeloid leukaemia (AML). The data regarding the alterations of endogenous thrombopoietin (TPO) regulation during the clinical course of AML are limited. The aim of this study was to investigate endogenous TPO dynamics in association with platelets during the clinical course of AML. We serially measured both TPO and platelets concurrently over the entire treatment period of newly diagnosed patients receiving both remission induction and consolidation chemotherapies. The median concentration of TPO in AML patients at the initial diagnosis was 469.71 pg/ml and increased significantly during the aplastic period due to remission induction chemotherapy (median: 1085.33 pg/ml) but then decreased to a level (median: 45.26 pg/ml) encountered in the healthy control subjects (median: 56.90 pg/ml). In the cytopenic period due to consolidation treatment, TPO level again increased significantly to a high level (median: 891.38 pg/ml) during the platelet nadir, but decreased toward normal (median: 100.75 pg/ml) after the thrombocytopenic period had elapsed. In conclusion, endogenous TPO levels exhibit an inverse fluctuation in relation to platelet counts during the clinical course of AML. Pharmacological stimulation of thrombopoiesis in AML with novel molecules, including the recombinant thrombopoietins and the small peptide agonists, should be based on a critical administration strategy that must consider the endogenous levels of TPO. TPO levels in distinct AML disease states may explain the unsuccessful recombinant TPO trials and could help to design better strategies for ‘pharmacological stimulation of thrombopoiesis’ in AML.

Raynaud's disease: Patient education as a primary nursing intervention

The terms Raynaud's disease and Raynaud's phenomenon are often used interchangeably to identify two distinct disease states that initially appear with similar symptoms but then have very different sequelae. Triggered primarily by cold weather, both conditions commonly result in a vasospastic response predominantly observed in the fingers and toes. A review of the relevant health care literature indicates that there is little, if any, information available on Raynaud's disease that would be of particular and specific interest to the nursing profession. So that they can provide appropriate patient teaching, nurses need to be familiar with the precipitating factors, signs and symptoms, evaluation methods, and treatments of Raynaud's disease. This article focuses specifically on Raynaud's disease, which affects many women but relatively few men. A historic perspective on this disease state is provided, and postulated pathophysiologic mechanisms for the onset of this condition are addressed. The patient who is experiencing symptoms of this disease may have complaints of pain and numbness particularly in the fingers. The nurse's primary role is patient education so that the onset of symptoms associated with this disease can be identified and minimized. A discussion of nursing implications with a focus on teaching is provided. A case study is presented of a patient with Raynaud's disease, which will serve to highlight and expound on key information provided throughout the text of this article.