Chronic intestinal pseudo-obstruction: pathogenesis, diagnosis and therapy

Chronic intestinal pseudo-obstruction (CIPO) is a rare disease in which a severe intestinal motility disorder impairs transit of chyme so that patients suffer from symptoms of a mechanical ileus without mechanical obstruction. CIPO may be a primary or secondary disorder due to muscular, neurologic, metabolic or endocrine disorders, but may also occur postinfectiously, postoperatively, following abdominal radiation or be caused by drugs or noxae. In severe cases, the typical history of (repeated) symptoms of mechanical obstruction leading to unsuccessful laparotomies will give key clues for diagnosis. If CIPO is suspected, mechanical obstruction must be searched for carefully by radiologic and endoscopic examinations. Histologic diagnosis usually demands full thickness biopsies of the intestinal wall. Small intestinal manometry allows diagnosis of CIPO even during oligosymptomatic intervals as well as differentiation between neuropathic and myopathic forms of the disease. The main therapeutic goals consist in: 1. Maintenance of an adequate nutritional state by oral and/or enteral nutrition; in severe cases home-parenteral nutrition may be required and particularly in children intestinal transplantation may be the ultima ratio. 2. Reconstitution of intestinal propulsion by prokinetic drugs. 3. Therapy of complications such as bacterial overgrowth and severe pain by antibiotics and specific surgical procedures. Unnecessary laparotomies should be strictly avoided because they may lead to adhesions and markedly complicate the clinical course.     

Thrombotic thrombocytopenic purpura: diagnosis, pathogenesis and modern therapy

Thrombotic thrombocytopenic purpura (TTP) is an uncommon multisystem disorder, sometimes associated with predisposing conditions such as pregnancy, cancer, exposure to certain drugs, bone marrow transplantation and HIV-1 infection. An abnormal interaction between the vascular endothelium and platelets which occurs in certain organs leads to thrombosis, endothelial proliferation, minimal inflammation and micro-angiopathic haemolysis. Recent studies suggest that endothelial cell perturbation and apoptosis caused by an as yet unknown plasma factor(s) may lead to the release of abnormal von Willebrand factor which facilitates the deposition of platelet microthrombi. Exchange transfusions of plasma or plasma-cryosupernatant remain the cornerstone of the treatment of TTP along with corticosteroids, platelet inhibitor drugs, vincristine and splenectomy. In most cases remissions can be attained, and cures are now common-although approximately one-half of the patients will relapse. While relapses are usually milder, they still carry a significant mortality and preventive therapies are not always effective.     

Hemophagocytic lymphohistiocytosis: An update on pathogenesis,diagnosis, and therapy

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening state of immune hyperactivation that arises in the setting of genetic mutations and infectious, inflammatory, or neoplastic triggers. Sustained, aberrant activation of cytotoxic CD8⁺ T cells and resultant inflammatory cytokine release are core pathogenic mechanisms. Key clinical features include high persistent fever, hepatosplenomegaly, blood cytopenia, elevated aminotransferase and ferritin levels, and coagulopathy. HLH is likely under-recognized, and mortality remains high, especially in adults; thus, prompt diagnosis and treatment are essential. Familial forms of HLH are currently treated with chemotherapy as a bridge to hematopoietic stem cell transplantation. HLH occurring in rheumatic disease (macrophage activation syndrome) is treated with glucocorticoids, IL-1 blockade, or cyclosporine A. In other forms of HLH, addressing the underlying trigger is essential. There remains a pressing need for more sensitive, context-specific diagnostic tools. Safer, more effective therapies will arise with improved understanding of the cellular and molecular mechanisms of HLH.     

Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management

The cardiotoxicity of anticancer agents can lead to significant complications that can affect patients being treated for various malignancies. The severity of such toxicity depends on many factors such as the molecular site of action, the immediate and cumulative dose, the method of administration, the presence of any underlying cardiac condition, and the demographics of the patient. Moreover, toxicity can be affected by current or previous treatment with other antineoplastic agents. Cardiotoxic effects can occur immediately during administration of the drug, or they may not manifest themselves until months or years after the patient has been treated. In this article we review commonly used chemotherapy agents, including several recently approved medications, for their propensity to cause cardiotoxicity. Further research will be required to more accurately predict which patients are at risk for developing cardiotoxicity. In addition, management plans, as well as strategies to reduce cardiotoxicity, need to be developed.     

Gold lung: recent developments in pathogenesis, diagnosis, and therapy

Gold lung is a hypersensitivity pneumonitis to gold-containing compounds. It can be distinguished from rheumatoid lung by its subacute or acute onset, diffuse interstitial and/or alveolar filling pattern on chest roentgenogram, presence of lymphocytes on BAL with an inverse helper/suppressor ratio, and response to withdrawal of gold and/or corticosteroid therapy. Other in vitro assays of gold hypersensitivity using peripheral blood lymphocytes are only sporadically positive and, therefore, of limited value in making the diagnosis. Physicians prescribing organic gold compounds should elicit pulmonary complaints throughout the duration of therapy. When patients receiving gold therapy present with signs and symptoms consistent with an acute or subacute hypersensitivity pneumonitis, the gold therapy should be withheld and a diagnostic workup initiated.     

Esophageal chest pain: current controversies in pathogenesis, diagnosis, and therapy

PURPOSE: To evaluate the importance of esophageal abnormalities as a potential cause of recurrent noncardiac chest pain. DATA IDENTIFICATION: We discuss the rapidly evolving new knowledge in this field after analyzing the literature in English published since 1979. STUDY SELECTION: We reviewed 117 articles on recurring chest pain and paid specific attention to the following nine controversial issues: the potential mechanisms of esophageal pain, the differentiation of cardiac and esophageal causes, the evaluation of new esophageal motility disorders, the use of esophageal tests in evaluating noncardiac chest pain, the usefulness of techniques for prolonged monitoring of intraesophageal pressure and pH, the relation of psychologic abnormalities to esophageal motility disorders, the possible mechanisms for decreased visceral pain thresholds in these patients, the relation of esophageal chest pain to the irritable bowel syndrome, and the appropriate therapies for these patients. RESULTS OF DATA SYNTHESIS: Through our review of the literature, we identified areas of concordance and disagreement. These areas are discussed and an overall perspective is provided. CONCLUSIONS: Continuing attempts to develop rational diagnostic and therapeutic approaches to patients with noncardiac chest pain should include a multidisciplinary approach involving basic scientists, gastroenterologists, psychologists, and other clinical experts in the field of pain research.     

Wilson disease: New insights into pathogenesis,diagnosis, and future therapy

Wilson disease is caused by disease-specific mutations of the copper transporting ATPase, ATP7B. The diagnosis is established by clinical and biochemical means, though advances in molecular diagnostics will someday permit de novo diagnosis. The patient may present with hepatic, neurologic, or psychiatric symptoms, or a combination of these. Both environmental and extragenic effects contribute to the varied phenotypic presentations of this disease. Patients can be treated effectively with chelating agents or zinc salts, or with liver transplantation. Liver cell transplant and gene therapy offer potential cures for this disorder, but at present only data from preclinical studies on animal models are available. Future advances in immunotolerization and gene therapy will likely enable human trials for treatment of this disorder and other genetic disorders of hepatic metabolism.     

Chronic pancreatitis: challenges and advances in pathogenesis, genetics, diagnosis, and therapy

Chronic pancreatitis (CP) is characterized by progressive pancreatic damage that eventually results in significant impairment of exocrine as well as endocrine functions of the gland. In Western societies, the commonest association of chronic pancreatitis is alcohol abuse. Our understanding of the pathogenesis of CP has improved in recent years, though important advances that have been made with respect to delineating the mechanisms responsible for the development of pancreatic fibrosis (a constant feature of CP) following repeated acute attacks of pancreatic necroinflammation (the necrosis-fibrosis concept). The pancreatic stellate cells (PSCs) are now established as key cells in fibrogenesis, particularly when activated either directly by toxic factors associated with pancreatitis (such as ethanol, its metabolites or oxidant stress) or by cytokines released during pancreatic necroinflammation. In recent years, research effort has also focused on the genetic abnormalities that may predispose to CP. Genes regulating trypsinogen activation/inactivation and cystic fibrosis transmembrane conductance regulator (CFTR) function have received particular attention. Mutations in these genes are now increasingly recognized for their potential 'disease modifier' role in distinct forms of CP including alcoholic, tropical, and idiopathic pancreatitis. Treatment of uncomplicated CP is usually conservative with the major aim being to effectively alleviate pain, maldigestion and diabetes, and consequently, to improve the patient's quality of life. Surgical and endoscopic interventions are reserved for complications such as pseudocysts, abscess, and malignancy.     

Diabetic cardiomyopathy: concept,heart function,and pathogenesis

The diabetic cardiomyopathy is a disease caused by diabetes and is characterised by the presence of diastolic and/or systolic left ventricular dysfunction. Diabetes may produce metabolic alterations, interstitial fibrosis, myocellular hypertrophy, microvascular disease and autonomic dysfunction. It is thought that all of them may cause cardiomyopathy. Other abnormalities that are usually associated with diabetes such as hypertension, coronary artery disease and nephropathy should be excluded before diagnosing diabetic cardiomyopathy. There is no evidence that diabetic cardiomyopathy alone can produce heart failure. However, subclinical ventricular dysfunction has been described in young asymptomatic diabetic patients without other diseases that could affect the cardiac muscle. In these cases we should consider that diabetes is the only cause of the myocardial disease. More studies are needed to know the natural history of diabetic cardiomyopathy.     

Malignant external otitis: insights into pathogenesis, clinical manifestations, diagnosis, and therapy

Malignant external otitis is an infection of the external ear canal, mastoid, and base of the skull caused by Pseudomonas aeruginosa. The condition occurs primarily in elderly patients with diabetes mellitus. Current theories on pathogenesis and anatomic correlations are reviewed. Severe, unrelenting otalgia and persistent otorrhea are the symptomatic hallmarks of the disease, whereas an elevated erythrocyte sedimentation rate is the only distinctive laboratory abnormality. Iatrogenic causes such as administration of broad-spectrum antibiotics and aural irrigation may play a predisposing role in high-risk populations. The disease can result in cranial polyneuropathies (with facial nerve [VII] paralysis being the most common) and death. The mainstay of treatment is administration of antipseudomonal antibiotics for four to eight weeks. Recurrence is common, and mortality remains at about 20 percent despite antibiotic therapy. Given the increasing longevity of diabetic patients, the frequency of this disease is increasing. Internists, family practitioners, and ambulatory care physicians must now be cognizant of the presenting symptoms, while infectious disease specialists and otolaryngologists need to be appraised of strides in diagnosis and therapy. The role of surgery should be minimized. Use of new diagnostic radiologic modalities and new antipseudomonal antibiotics discussed in this review should lead to improved outcome.     

Diabetic nephropathy in type 1 diabetes: a review of early natural history,pathogenesis, and diagnosis

Diabetic nephropathy constitutes a devastating complication in patients with type 1 diabetes mellitus, and its diagnosis is traditionally based on microalbuminuria. The aim of this review is to update through the medical literature the suggested early natural course of diabetic nephropathy, the theories behind the pathways of its pathogenesis, and its diagnosis. Poor glycemic control, dyslipidemia, smoking, advanced glycation end products, and environmental and genetic clues play an important role in the development of diabetic nephropathy. Microalbuminuria has been traditionally considered as a primary early marker of microvascular complication unraveling the risk for progress to the advanced stages of chronic kidney disease, but because of our inability to make an early diagnosis of diabetic nephropathy in young patients as well as nonalbuminuric diabetic nephropathy, recently, other additional markers of renal injury like serum and urinary neutrophil gelatinase–associated lipocalin, chitinase‐3–like protein 1, cystatin C, and plasma growth differentiation factor 15 have been proposed to unmask early renal dysfunction, even before microalbuminuria supervenes. Copyright © 2016 John Wiley & Sons, Ltd.     

Update on the pathogenesis,diagnosis, and therapy of AIDs-related lymphoma

AIDS-related non-Hodgkin’s lymphoma (ARL) is an opportunistic malignancy that foreshortens life more than any other commonly occurring HIV-associated cancer. Treatment strategies include low-dose chemotherapy, chemotherapy given with antiretroviral therapy, and infusional chemotherapy regimens. Rituximab, an anti-CD20 monoclonal antibody, has been found to be useful in non-HIV-associated lymphomas and is of interest in ARL as well. Since the advent of highly active antiretroviral therapy, the ARL incidence and survival has changed. This paper reviews the epidemiologic, biologic, and clinical features of ARL with the aim of presenting a cohesive overview of these elements.     

Central nervous system toxoplasmosis in HIV pathogenesis, diagnosis, and therapy

In patients with HIV, Toxoplasma gondii is the most frequent infectious cause of focal brain lesions. Particularly in advanced HIV disease, it can cause significant morbidity and mortality. Current clinical practice involves empiric therapy with pyrimethamine and sulfadiazine, upon a presumptive diagnosis of toxoplasmic encephalitis, based on serologic, clinical, and radiological features. This approach continues to evolve, as new diagnostic strategies, such as the use of immunoglobulin G antibody titers and polymerase chain reaction, prophylaxis against opportunistic infections, and highly active antiretroviral therapy—HAART—come into play. Primary and secondary prophylaxis are the mainstay of treatment. There remains a continuing need for development of new anti-Toxoplasma therapy.     

Recent developments in pathogenesis,diagnosis and therapy of Barrett's esophagus

The burden of illness from esophageal adenocarcinoma continues to rise in the Western world, and overall prognosis is poor. Given that Barrett’s esophagus (BE), a metaplastic change in the esophageal lining is a known cancer precursor, an opportunity to decrease disease development by screening and surveillance might exist. This review examines recent updates in the pathogenesis of BE and comprehensively discusses known risk factors. Diagnostic definitions and challenges are outlined, coupled with an in-depth review of management. Current challenges and potential solutions related to screening and surveillance are discussed. The effectiveness of currently available endoscopic treatment techniques, particularly with regards to recurrence following successful endotherapy and potential chemopreventative agents are also highlighted. The field of BE is rapidly evolving and improved understanding of pathophysiology, combined with emerging methods for screening and surveillance offer hope for future disease burden reduction.     

Leptospirosis: pathogenesis, immunity, and diagnosis

PURPOSE OF REVIEW: Leptospirosis is among the most important zoonotic diseases worldwide. Completion of the genomic sequences of leptospires has facilitated advances in diagnosis and prevention of the disease, and yielded insight into its pathogenesis. This article reviews this research, emphasizing recent progress. RECENT FINDINGS: Leptospirosis is caused by a group of highly invasive spiral bacteria (spirochetes) that can infect both people and animals. Spirochetes can survive in the environment and host, and therefore outer membrane and secretory proteins that interact with the host are of considerable interest in leptospire research. The genetic approach to studying pathogenesis is hindered by fastidious growth of pathogenic leptospires. Integrated genomic and proteomic approaches, however, have yielded enhanced understanding of the pathogenesis of leptospirosis. Furthermore, studies of innate immune response to the organism have enhanced our understanding of host susceptibility and resistance to infection. In-silico analysis and high-throughput cloning and expression have had major impacts on efforts to develop vaccine candidates and diagnostic reagents. SUMMARY: In the future, we must effectively utilize the wealth of genetic information to combat the disease. More studies into genetics, immune mechanisms that may be exploited to prevent leptospirosis, and pathogenesis of the disease are necessary.