A gene-based recessive diplotype exome scan discovers FGF6, a novel hepcidin-regulating iron-metabolism gene.

Standard analyses applied to genome-wide association data are well designed to detect additive effects of moderate strength. However, the power for standard genome-wide association study (GWAS) analyses to identify effects from recessive diplotypes is not typically high. We proposed and conducted a gene-based compound heterozygosity test to reveal additional genes underlying complex diseases. With this approach applied to iron overload, a strong association signal was identified between the fibroblast growth factor-encoding gene, FGF6, and hemochromatosis in the central Wisconsin population. Functional validation showed that fibroblast growth factor 6 protein (FGF-6) regulates iron homeostasis and induces transcriptional regulation of hepcidin. Moreover, specific identified FGF6 variants differentially impact iron metabolism. In addition, FGF6 downregulation correlated with iron-metabolism dysfunction in systemic sclerosis and cancer cells. Using the recessive diplotype approach revealed a novel susceptibility hemochromatosis gene and has extended our understanding of the mechanisms involved in iron metabolism.

Abdominal Physical Signs and Medical Eponyms: Part I. Percussion, 1871-1900.

BACKGROUND: Percussion is derived from the Latin word to hear and to touch. Percussion of the abdomen is used to detect areas of tenderness, dullness within an area of tenderness suggestive of a mass, shifting dullness representing fluid or blood, splenic, hepatic and bladder enlargement, and free air in the peritoneum. Covered are abdominal signs of percussion attributed as medical eponyms from the time-period beginning in the mid-late nineteenth century. Described is historical information behind the sign, descriptions of the sign, and implication in modern clinical practice. DATA SOURCES: PubMed, Medline, online Internet word searches, textbooks, and references from other source text. PubMed was searched using the Medical Subject Heading (MeSH) of the name of the eponyms and text words associated with the sign. CONCLUSION: Percussion signs defined as medical eponyms were important discoveries adopted by physicians prior to the advent of radiographs and other imaging and diagnostic techniques. The signs perfected during this time-period provided important clinical cues as to the presence of air within the peritoneum or rupture of the spleen.

Abdominal Physical Signs and Medical Eponyms: Part II. Percussion and Auscultation, 1924-1980.

BACKGROUND: Percussion and auscultation are derived from the Latin words to touch and hear, respectively. Covered are abdominal percussion signs and ausculatory signs discovered from 1924 to 1980. Signs ascribed as medical eponyms pay homage to these physicians who provided new and unique insights into disease. DATA SOURCES: PubMed, Medline, online Internet word searches, textbooks, and references from other source text. PubMed was searched using the Medical Subject Heading (MeSH) of the name of the eponyms and text words associated with the sign. CONCLUSION: Many of these signs have been discarded because of modern imaging and diagnostic techniques. When combined with a high clinical suspicion, positive results using percussion combined with palpation is a useful bedside technique in detecting splenic enlargement. Thus, some of these maneuvers remain important bedside techniques that skilled practitioners should master, and along with a meaningful history, provide relevant information to diagnosis. It is through learning about these signs that we gain a sense of humility on the difficulty physicians faced prior to the advent of techniques that now allow us an easier way to visualize and diagnose the underlying disease processes.

Pentostatin, Cyclophosphamide, and Rituximab Followed by Alemtuzumab for Relapsed or Refractory Chronic Lymphocytic Leukemia: A Phase 2 Trial of the ECOG-Acrin Cancer Research Group (E2903).

Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) may benefit from salvage chemoimmunotherapy (CIT). To explore further the use of CIT in the pre-novel agent era, ECOG-ACRIN undertook a phase 2 trial (E2903) for R/R CLL utilizing pentostatin, cyclophosphamide, and rituximab (PCR) followed by a consolidation course of alemtuzumab. This trial enrolled 102 patients with a median age of 64 years. Treatment consisted of 6 cycles of PCR followed by alemtuzumab for either 4 or 18 weeks depending on the initial response to PCR. The overall response after PCR (complete remission, CR, nodular partial remission, nPR, and partial remission, PR) was 55%. Major responses (CR or nPR) were achieved in 6%. The median overall survival (OS) and the median progression-free survival were 28 and 12 months, respectively. The most serious nonlethal adverse events were myelosuppression, febrile neutropenia, fatigue, nausea, and hyponatremia. PCR is an effective and well-tolerated nucleoside-based regimen for heavily pretreated CLL patients with R/R disease. The addition of alemtuzumab to CLL patients with a minor response (PR) or stable disease did not result in a significant number of higher responses (CR or nPR) nor an improvement in OS.

Abdominal Physical Signs of Inspection and Medical Eponyms.

BACKGROUND: An eponym in clinical medicine is an honorific term ascribed to a person(s) who may have initially discovered or described a device, procedure, anatomical part, treatment, disease, symptom, syndrome, or sign found on physical examination. Signs, although often lacking sufficient sensitivity and specificity, assist in some cases to differentiate and diagnose disease. With the advent of advanced technological tools in radiological imaging and diagnostic testing, the importance of inspection, the initial steps taught during the physical examination, is often overlooked or given only cursory attention. Nevertheless, in the era of evidence-based and cost-effective medicine, it becomes compelling, and we contend that a meticulously performed history and physical examination, applying the basic tenets of inspection, remains paramount prior to obtaining appropriate diagnostic tests. DATA SOURCES: PubMed, Medline, online Internet word searches and bibliographies from source text and textbooks. PubMed was searched using the Medical Subject Heading (MeSH) of the name of the eponyms and text words associated with the sign. CONCLUSIONS: We describe the historical aspect, clinical application, and performance of medical eponymous signs of inspection found on physical examination during the 18th to 20th centuries.

Abdominal Physical Signs and Medical Eponyms: Part III. Physical Examination of Palpation, 1926-1976.

BACKGROUND: This paper describes medical eponyms associated with abdominal palpation from the period 1926-1976. Despite opposition by some, eponyms are a long standing tradition and widely used in medicine. The techniques may still be useful in some cases, assisting in the selection of an appropriate and cost-effective approach to patient care. In this piece, we cover signs named in honor of physicians who contributed to medicine by developing new palpatory techniques in an attempt to better diagnose disease of the abdominal wall, umbilicus, gallbladder, pancreas, and appendix. DATA SOURCES: PubMed, Medline, online Internet word searches, textbooks, and references from other source texts. PubMed was searched using the Medical Subject Heading (MeSH) of the name of the eponyms and text words associated with the sign. CONCLUSION: We describe brief historical background information about the physician who reported the sign, original description of the sign, and its clinical application and implication into today's medical practice.

Abdominal Physical Signs and Medical Eponyms: Part II. Physical Examination of Palpation, 1907-1926.

BACKGROUND: Abdominal palpation is an important clinical skill used by physicians to detect the cause of the underlying disease. Abdominal physical signs reported as medical eponyms are sometimes helpful in supporting or confirming clinical suspicion of a diagnosis. With the advent of advanced and rapid imaging techniques physicians often know the diagnosis prior to setting their hands on patients. Nevertheless, knowledge of these signs may still remain important in settings where imaging may not be readily available and importantly provide deeper insights into the mechanism of disease. In this paper, described are medical eponyms associated with abdominal palpation from the period 1907-1926. DATA SOURCES: PubMed, Medline, on-line Internet word searches, textbooks, and references from other source text were used as the data source. PubMed was searched using the Medical Subject Heading (MeSH) of the name of the eponyms and text words associated with the sign. CONCLUSION: We describe brief historical background information about the physician who reported the sign, original description of the sign, and its clinical application and implication into today's medical practice.

Abdominal Physical Signs and Medical Eponyms: Movements and Compression.

BACKGROUND: Prior to the advent of modern imaging techniques, maneuvers were performed as part of the physical examination to further assess pathological findings or an acute abdomen and to further improve clinicians' diagnostic acumen to identify the site and cause of disease. Maneuvers such as changing the position of the patient, extremity, or displacing through pressure a particular organ or structure from its original position are typically used to exacerbate or elicit pain. Some of these techniques, also referred to as special tests, are ascribed as medical eponym signs. DATA SOURCES: PubMed, Medline, online Internet word searches, textbooks and references from other source text. PubMed was searched using the Medical Subject Heading (MeSH) of the name of the eponyms and text words associated with the sign. CONCLUSION: These active and passive maneuvers of the abdomen, reported as medical signs, have variable performance in medical practice. The lack of diagnostic accuracy may be attributed to confounders such as the position of the organ, modification of the original technique, or lack of performance of the maneuver as originally intended.

Flushing Disorders Associated with Gastrointestinal Symptoms: Part 1, Neuroendocrine Tumors, Mast Cell Disorders and Hyperbasophila.

Flushing is the subjective sensation of warmth accompanied by visible cutaneous erythema occurring throughout the body with a predilection for the face, neck, pinnae, and upper trunk where the skin is thinnest and cutaneous vessels are superficially located and in greatest numbers. Flushing can be present in either a wet or dry form depending upon whether neural-mediated mechanisms are involved. Activation of the sympathetic nervous system results in wet flushing, accompanied by diaphoresis, due to concomitant stimulation of eccrine sweat glands. Wet flushing is caused by certain medications, panic disorder and paroxysmal extreme pain disorder (PEPD). Vasodilator mediated flushing due to the formation and release of a variety of biogenic amines, neuropeptides and phospholipid mediators such as histamine, serotonin and prostaglandins, respectively, typically presents as dry flushing where sweating is characteristically absent. Flushing occurring with neuroendocrine tumors accompanied by gastrointestinal symptoms is generally of the dry flushing variant, which may be an important clinical clue to the differential diagnosis. A number of primary diseases of the gastrointestinal tract cause flushing, and conversely extra-intestinal conditions are associated with flushing and gastrointestinal symptoms. Gastrointestinal findings vary and include one or more of the following non-specific symptoms such as abdominal pain, nausea, vomiting, diarrhea or constipation. The purpose of this review is to provide a focused comprehensive discussion on the presentation, pathophysiology, diagnostic evaluation and management of those diseases that arise from the gastrointestinal tract or other site that may cause gastrointestinal symptoms secondarily accompanied by flushing. This review is divided into two parts given the scope of conditions that cause flushing and affect the gastrointestinal tract: Part 1 covers neuroendocrine tumors (carcinoid, pheochromocytomas, vasoactive intestinal polypeptide, medullary carcinoma of the thyroid), polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS), and conditions involving mast cells and basophils; while Part 2 covers dumping syndrome, mesenteric traction syndrome, rosacea, hyperthyroidism and thyroid storm, anaphylaxis, panic disorders, paroxysmal extreme pain disorder, and food, alcohol and medications.

Flushing Disorders Associated with Gastrointestinal Symptoms: Part 2, Systemic Miscellaneous Conditions.

Flushing disorders with involvement of the gastrointestinal tract represent a heterogeneous group of conditions. In part 1 of this review series, neuroendocrine tumors (NET), mast cell activation disorders (MCAD), and hyperbasophilia were discussed. In this section we discuss the remaining flushing disorders which primarily or secondarily involve the gastrointestinal tract. This includes dumping syndrome, mesenteric traction syndrome, rosacea, hyperthyroidism and thyroid storm, anaphylaxis, panic disorders, paroxysmal extreme pain disorder, and food, alcohol and medications. With the exception of paroxysmal pain disorders, panic disorders and some medications, these disorders presents with dry flushing. A detailed and comprehensive family, social, medical and surgical history, as well as recognizing the presence of other systemic symptoms are important in distinguishing the different disease that cause flushing with gastrointestinal symptoms.

Abdominal Physical Signs and Medical Eponyms: Physical Examination of Palpation Part 1, 1876-1907.

BACKGROUND: Abdominal palpation is a difficult skill to master in the physical examination. It is through the tactile sensation of touch that abdominal tenderness is detected and expressed through pain. Its findings can be used to detect peritonitis and other acute and subtle abnormalities of the abdomen. Some techniques, recognized as signs or medical eponyms, assist clinicians in detecting disease and differentiating other conditions based on location and response to palpation. Described in this paper are medical eponyms associated with abdominal palpation from the period 1876 to 1907. DATA SOURCES: PubMed, Medline, on-line Internet word searches, textbooks and references from other source text were used as the data source. PubMed was searched using the Medical Subject Heading (MeSH) of the name of the eponyms and text words associated with the sign. CONCLUSION: We present brief historical background information about the physician who reported the sign, original description of the sign, and its clinical application and implication in today's medical practice.

The Clinical Significance of Relative Bradycardia.

INTRODUCTION: Relative bradycardia is a poorly understood paradoxical phenomenon that refers to a clinical sign whereby the pulse rate is lower than expected for a given body temperature. OBJECTIVE: To provide an overview and describe infectious and noninfectious causes of relative bradycardia. METHODS: PubMed and Medline databases were searched using individual and Medical Subject Headings terms including relative bradycardia, fever, pulse-temperature dissociation and pulsetemperature deficit in human studies published from inception to October 2, 2016. The causes and incidence of relative bradycardia were reviewed. RESULTS: Relative bradycardia is found in a wide variety of infectious and noninfectious diseases. The pathogenesis remains poorly understood with proposed mechanisms including release of inflammatory cytokines, increased vagal tone, direct pathogenic effect on the myocardium, and electrolyte abnormalities. The incidence of this sign varies widely, which may be attributable to multiple factors, including population size, time course for measuring pulse and temperature, and lack of a consistent definition used. The fact that this sign is not consistently identified in case series suggests that relative bradycardia is caused by mechanisms presumably involving or influenced by pathogen and host factors. CONCLUSIONS: Relative bradycardia is a sensitive but nonspecific clinical sign that may be an important bedside tool for narrowing the differential diagnosis of potential infectious and noninfectious etiologies. Recognizing this relationship may assist the clinician by providing bedside clinical clues into potential etiologies of disease, particularly in the setting of infectious diseases and in circumstances when other stigma of disease is absent.

A systematic review of mobility/immobility in thromboembolism risk assessment models for hospitalized patients.

Hospitalized patients are at risk of venous thromboembolism (VTE) and prophylaxis is often suboptimal due to difficulty in identifying at-risk patients. Simple and validated risk-assessment models (RAMs) are available to assist clinicians in identifying patients who have a high risk for developing VTE. Despite the well-documented association of immobility with increased risk of thrombosis, immobility is not consistently defined in clinical studies. We conducted a systematic review of published VTE RAMs and used objective criteria to determine how the term immobility is defined in RAMs. We identified 17 RAMs with six being externally validated. The concept of immobility is vaguely described in different RAMs, impacting the validity of these models in clinical practice. The wide variability in defining mobility in RAMs precluded its accurate clinical application, further limiting generalization of published RAMs. Externally validated RAMs with clearly defined qualitative or quantitative terms of immobility are needed to assess VTE risk in real-time at the point-of-care.

Thromboembolic complications following a first isolated episode of superficial vein thrombosis: a cross-sectional retrospective study.

Superficial vein thrombosis (SVT) may be associated with complications such as venous thromboembolism (VTE) and recurrent SVT. The purpose of this study was to explore risk factors among patients with a first isolated episode of SVT (index SVT) involving upper and lower extremities and to estimate the prevalence of VTE complications within 1 year of index SVT. Retrospective chart review of electronic records at Marshfield Clinic in Wisconsin identified 381 subjects with a first isolated SVT diagnosis (male/female: 170/211; median age 59.4 years). Patients were stratified based on whether they did (n = 44; 11.5 %) or did not (n = 337; 88.5 %) experience VTE complications and whether they did (n = 25; 6.6 %) or did not (n = 356; 93.4 %) experience pulmonary embolism (PE) and/or deep vein thrombosis (DVT) within 1 year of index SVT. There were 49 complications among 44 patients; these included DVT (n = 18, 36.7 %), propagation of SVT (n = 18, 36.7 %), PE (n = 9, 18.4 %), new SVT at different location (n = 3, 6.1 %), and recurrent SVT (n = 1, 2.0 %). Univariate analysis of all VTE complications identified seven potential risk factors and similar analysis of PE/DVT complications identified eight potential risk factors, with six common risk factors identified in both analyses. Multivariate analysis identified indwelling venous catheter 30 days prior to SVT (p = 0.044), cancer history with treatment in the previous year (p = 0.001), and non-surgical trauma 7 days prior to SVT (p < 0.001) as independent risk factors for PE/DVT complications. Independent risk factors identified in the current study may convey greater risk for VTE complications, especially PE/DVT, following an initial isolated SVT episode.

Reinitiating warfarin: relationships between dose and selected patient, clinical and hospital measures.

BACKGROUND: Warfarin is an oral anticoagulant used in the long-term treatment/prevention of venothromboembolic disease. Patients undergoing elective surgical and non-surgical procedures may require temporary warfarin discontinuation followed by reinitiation after their procedure. Because little information is available regarding best methods for warfarin reinitiation, we investigated current practices to inform management decisions. METHODS: Subjects were required to have a known and stable warfarin dose prior to discontinuation, which was operationalized by requiring, within 7-days prior to discontinuation, that they have at least one INR in therapeutic range (2.0-3.5), no INR(s) out of range, and no more than a 15% change in warfarin dose. Stable dose prior to discontinuation was defined as the average daily dose received in the 7 days immediately prior to discontinuation. Reinitiation dose was defined as the average daily dose received in the first 3 days after warfarin was restarted. Subjects were divided into three groups based on whether they received approximately the same, a higher, or a lower dose at reinitiation and were also grouped by calendar time into three distinct periods that reflected differing levels of availability of electronic and patient care data that may impact reinitiation dose decisions. These groupings facilitated analyses and descriptions of trends in reinitiation dosing and supported other analyses, including tests for association between dose group and selected subject demographic, clinical, medication and hospitalization measures. All study data were abstracted from Marshfield Clinic electronic patient care and administrative databases and electronic patient care databases from Ministry St. Joseph's Hospital (Marshfield, WI). RESULTS: We identified 205 subjects with warfarin temporarily discontinued between 1994 and 2012: 99 subjects in same dose group, 32 subjects in the low group, and 74 subjects in the high group. Because relatively wide differences were observed in the proportion of same dose subjects during more recent years (2007-2012) compared to earlier years (54% vs 35%), we focused our analyses on this recent period, which included 140 subjects. Review of physician notes and other documents yielded virtually no information about reasons for reinitiation dose decisions. In addition, tests for association between reinitiation dose group and subject demographic, clinical, medication and hospital measures were uniformly uninformative. CONCLUSIONS: We observed varied dosing strategies for reinitiating patients on warfarin and, in more recent years, an apparent trend toward reinitiating patients on the same dose. However we could not associate dosing strategy with specific patient demographic, clinical, medication or hospital factors. Many factors influence whether a physician reinitiates a patient at a different dose than his/her prior stable warfarin dose. However, in the absence of clinical indications for modification, we believe patients with a previously established effective dose should be reinitiated at that same dose following temporary warfarin discontinuation.

A Review of Clinical Signs Related to Ecchymosis.

Ecchymosis is a large area of discoloration caused by extravasation of blood into the subcutaneous tissue. It is an objective physical finding that may provide valuable clues as to its possible etiology. Ecchymosis is associated with eponyms based on the physician who first described the physical findings, which can be divided into 4 anatomical categories: base of the skull, abdominal wall and retroperitoneum, groin and scrotum, and lower extremity. Classic external signs and eponyms associated with ecchymosis are reviewed. Knowledge of these signs on physical examination may prove to be a useful clue directing the examiner to consider potentially serious causes of disease.

Factors that affect rate of INR decline after warfarin discontinuation.

BACKGROUND: Despite vast literature on warfarin, optimal strategies for temporarily discontinuing and restarting warfarin have not been established. To improve warfarin discontinuation processes, we investigated known medical and genetic factors that influence stable warfarin dose to determine how well they predict the time until patients become subtherapeutic after discontinuing warfarin. METHODS: This was a retrospective cohort study of patients who temporarily discontinued warfarin before an elective procedure andhad at least 2 international normalized ratio (INR) values available during the discontinuation period. Data abstracted included date of discontinuation, warfarin dose, INR values, body surface area, gender, age, indication for warfarin, current medications, eGFR, and presence of bridging therapy with heparin. DNA variants were tested in CYP2C9, VKORC1, and CYP4F2 genes. Subjects were excluded if they received vitamin K, fresh frozen plasma, or prothrombin complexes to reverse anticoagulation. Asymptotic regression models were used to approximate decline in INR during warfarin clearance. Spearman correlations and Kruskal-Wallis tests were used to characterize associations of model estimates with quantitative variables and for group comparisons, respectively. RESULTS: Other than the expected association with baseline INR, correlations of model parameter estimates with clinical variables were generally weak and not statistically significant. The strongest associations with slope were with serum creatinine and eGFR. There were no significant associations with CYP2C9, VKORC1, or CYP4F2 DNA variants, but there were few subjects combined in the nonwild groups for CYP2C9. Estimated slope showed moderate correlation with observed dose. CONCLUSION: Known clinical and genetic predictors of therapeutic dose were not found to be strongly associated with the slope of INR decline after warfarin discontinuation.

Symptomatic factor XIII deficiency with normal urea solubility test.

BACKGROUND: Factor XIII deficiency is a rarely encountered bleeding disorder traditionally identified by clot dissolution in 5 molar urea (urea solubility test). METHODS: We report a patient with delayed post-surgical bleeding characteristic of factor XIII deficiency with a normal urea solubility test. RESULTS: Factor XIII deficiency was identified by an automated assay that measured factor XIII antigen. The patient was successfully treated with cryoprecipitate. CONCLUSIONS: Patients with excessive bleeding with normal screening tests should be tested for factor XIII using a sensitive assay procedure. The urea solubility assay for factor XIII should be discontinued due to its lack of sensitivity.

Mirtazapine and mefloquine therapy for non-AIDS-related progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the human nervous system caused by the JC virus. We report what is, to the best of our knowledge, the second reported case using a combination of mefloquine and mirtazapine in a patient with non-AIDS-related PML with a good clinical outcome. Conversely, the recent trial of mefloquine in 21 patients with AIDS and 3 without AIDS failed to show a reduction of JC viral DNA levels in the cerebral spinal fluid. However, the positive clinical response seen in our patient after the initiation of this combination therapy suggests that further studies in the form of randomized controlled trials for the treatment of non-AIDS-related PML are warranted.

Multilocular thymic cyst with epithelioid granulomata of unknown etiology: a radiologic and histopathologic correlation.

Thymic cysts (congenital or acquired) are believed to account for 3% to 5% of all mediastinal masses. Multilocular thymic cysts are an acquired reactive inflammatory process arising within the thymus gland and are less common than the congenital unilocular type. Multilocular cysts have been reported in association with a variety of neoplastic, autoimmune, and infectious conditions. We report a case of a 23-year-old white man who presented with a 2-week history of progressive right-sided shoulder and chest pain. He was found to have an anterior mediastinal mass involving the thymus. This case of multilocular thymic cyst is particularly unique due to the presence of abundant epithelioid granulomata within the cyst, a finding that has not previously been emphasized as a histologic feature of these lesions, and one that expands the histopathologic differential diagnosis, warranting exclusion of infectious and autoimmune etiologies.