Understanding insulin resistance. What are the clinical implications?

Insulin resistance is an important clinical issue in patients with other prominent components of metabolic syndrome, such as central adiposity and diabetes. However, its presence may be less evident in patients who are neither obese nor diabetic. Is measurement of insulin resistance important in clinical practice? How might its presence change management in individual patients? In this concise review, Dr Sivitz discusses the underlying mechanisms involved in insulin resistance, the issues surrounding assessment, and the implications for management in patients in whom insulin resistance is either detected or suspected.     

Optimal diagnosis and management of common nail disorders

Nail conditions are not only aesthetic concerns, and nail changes may be a clue to an underlying systemic diseases or infection. Without timely treatment, nail diseases can continue to worsen and significantly impair performance of daily activities and reduce quality of life. Examination of the nails is essential at every medical visit, and may uncover important findings. Brittle nail syndrome, onychomycosis, paronychia, nail psoriasis, longitudinal melanonychia, Beau’s lines, onychomadesis and retronychia are common nail disorders seen in clinical practice. These conditions stem from infectious, inflammatory, neoplastic and traumatic aetiologies. Though each nail condition presents with its own distinct characteristics, the clinical findings may overlap between different conditions, resulting in misdiagnosis and treatment delays. Patients can present with nail plate changes (e.g. hyperkeratosis, onycholysis, pitting), discolouration, pain and inflammation. The diagnostic work-up of nail disease should include a detailed history and clinical examination of all 20 nail units. Dermoscopy, diagnostic imaging and histopathologic and mycological analyses may be necessary for diagnosis. Nail findings concerning for malignancy should be promptly referred to a dermatologist for evaluation and biopsy. Nail disease management requires a targeted treatment approach. Treatments include topical and/or systemic medications, discontinuation of offending drugs or surgical intervention, depending on the condition. Patient education on proper nail care and techniques to minimize further damage to the affected nails is also important. This article serves to enhance familiarity of the most common nail disorders seen in clinical practice. It will highlight the key clinical manifestations, systematic approaches to diagnosis and treatment options for each nail condition to improve diagnosis and management of nail diseases, as well as patient outcomes.

Key messages

• Nail disease is not only a cosmetic issue, as nail changes can indicate the presence of a serious underlying systemic disease, infection or malignancy.
• Nail pain and changes associated with NP are physically and emotionally distressing and may contribute to functional impairment and diminished quality of life.
• LM is a hallmark sign of subungual melanoma and this finding warrants further investigation to rule out malignancy.

     

Ventricular arrhythmia: management guidelines for the primary health care setting

Ventricular arrhythmia is a common problem in the ambulatory setting. Ventricular arrhythmias that appear to be similar on the electrocardiograph may have different prognostic significance, depending on the patient's age and the presence of underlying heart disease or ventricular dysfunction. The ultimate goal in the care of any patient with ventricular arrhythmia is prevention of sudden cardiac death. Patients can usually be classified into one of five diagnostic categories, based on symptoms and evidence of underlying heart disease. This article discusses the classification of ventricular arrhythmias as either benign, potentially malignant or malignant. The risks of antiarrhythmic therapy and specific management plans for each of the five diagnostic categories are provided. These management plans are meant to serve as a framework for the clinician who provides primary care to these patients. An explanation of terms used commonly in the interpretation of ventricular arrhythmias is included, as well as guidelines for the assessment of patients with ventricular arrhythmias.     

Diagnostic de l’embolie pulmonaire au service des urgences

Pulmonary embolism (PE) is the third most common acute cardiovascular disease after myocardial infarction and stroke. Nevertheless, the diagnosis still remains difficult in the emergency setting. Clinical suspicion is raised by risk factors and often unspecific symptoms. The next step is to determine the pretest probability of PE either with validated scores or clinical gestalt. This probability is further refined with various diagnostic tests for which indications and limitations should be known. This systematic approach allows an efficient diagnosis of PE, avoiding the overconsumption of tests. The aim of our work is to review the practical diagnostic approach of PE at the emergency department in hemodynamically stable patients.     

Mutations in the Kir6.2 subunit of the KATP channel and permanent neonatal diabetes: new insights and new treatment

Permanent neonatal diabetes (PNDM) is diagnosed in the first three months of life and is a major management problem as patients require lifelong insulin injections. Recently, activating mutations in the KCNJ11 gene which encodes the Kir6.2 subunit of the KATP channels in the pancreatic beta-cells were found to be an important cause of PNDM. The mutated KATP channels do not close in the presence of adenosine triphosphate (ATP) so the beta-cell membrane is hyperpolarized and insulin secretion does not occur. Some patients have DEND syndrome (developmental delay, epilepsy and neonatal diabetes) with the neurological features arising from mutated KATP channels in muscle, nerve and brain. Defining a genetic aetiology has not only given insights into clinical classification and disease mechanism, but has also influenced treatment. Sulphonylureas, by binding the sulphonylurea receptor, can close the KATP channel. This has led to patients who were insulin-dependent being able to discontinue insulin injections and achieve excellent control with sulphonylurea tablets. In this article we discuss the work that established Kir6.2 mutations as a common cause of neonatal diabetes, the clinical features, the underlying mechanism and the impact on patient treatment.     

Redefining the clinical management of type 2 diabetes: matching therapy to pathophysiology

Conventional treatments for type 2 diabetes do not provide adequate glycaemic control to prevent the long-term progression of the disease. The introduction of increasingly intensive therapeutic regimens in stepwise management strategies aims to maintain glycaemic control in the face of progressive deterioration in beta-cell function. However, such an approach does not entirely address the underlying disease mechanisms. Although much remains unclear about the aetiology of type 2 diabetes, both beta-cell dysfunction and insulin resistance play important roles, and there is a complex, dynamic interaction between these two abnormalities. Growing evidence suggests that treatments that can reverse insulin resistance and improve beta-cell function may be able to slow or prevent the progression of the disease. The clinical management of type 2 diabetes therefore needs to be re-examined and redefined to reflect new insights into the underlying pathogenetic mechanisms, including consideration of the potential benefits of early, aggressive intervention to counter both beta-cell dysfunction and insulin resistance.     

Pharmacological options in the management of orthostatic hypotension in older adults

Orthostatic hypotension (OH) is a common disorder in older adults with potentially serious clinical consequences. Understanding the key underlying pathophysiological processes that predispose individuals to OH is essential when making treatment decisions for this group of patients. In this article, we discuss the key antihypotensive agents used in the management of OH in older adults. Commonly, midodrine is used as a first-line agent, given its supportive data in randomized, controlled trials. Fludrocortisone has been evaluated in open-label trials and has long-established usage in clinical practice. Other agents are available and in clinical use, either alone or in combination, but larger randomized trial evaluations are yet to be published. It is important to bear in mind that a patient may be taking medications that predispose to or exacerbate the symptoms of OH. Withdrawal of such medications, where possible, should be considered before commencing other pharmacological agents that attenuate the symptoms of OH.     

Treatment of chronic dysimmune polyneuropathies

Chronic dysimmune neuropathies are less common than Guillain-Barré syndrome (GBS). They mainly comprise chronic idiopathic demyelinating polyneuropathy (CIDP), multifocal motor neuropathy with persistent conduction blocks (MMNCB) and polyneuropathy associated with monoclonal gammopathy. However, as GBS, they are considered to be immune-mediated disorders and they may respond to various immunosuppressive treatments, such as corticosteroids, plasma exchanges (PE) or intravenous immunoglobulins (IVIg). The first step is to characterize these neuropathies on clinical, electrophysiological and sometimes immunochemical criteria, because the response to treatment may be different according to the type of neuropathy. For example, polyneuropathy associated with IgM monoclonal gammopathy does not respond to steroids and MMNCB may worsen under PE, while CIDP may respond either to steroids, PE or IVIg. The second step is to choose the type and the regimen of the treatment. Some neurological conditions may require only short-term therapy, for example in relapsing CIDP, whereas other conditions may require long-term therapy.     

Bronichiloitis obliterms-current concepts

We review current concepts abut the clinical manifestations,diagnosisand treatment of patients with bronchiolitis obliterans (BO)with emphasis on clinical/pathological correlations and recentdevelopments. BO is a relatively rare disease, but its incidenceis probably higher than generally believed and is continuouslyrising, partly because of better recognition, but also becauseof increased exposure to industrial fumes, and its occurrencein lung transplantation. BO is characterized histologicallyby varying degrees of obliteration of the lumen of the respiratorybronchioles by organizing connective tissue often extendinginto the alveoli (‘proliferative’ BO with organizingpneumoni+BOOP) or by more extensive fibrosis and scarring ofthe more proximal, conductive bronchioles (‘constrictive’BO). Diverse clinical conditions have been associated with thedevelopment of BO, notably viral and mycoplasma infection, toxicfume exposure and immune reactions in the setting of a collagenvascular disease, drug reaction or organ transplantation. Theclinical course and features of BO may vary considerably accordingto the aetiology, histological pattern and stage of the disease.The most common presentation is that of a progressive dry coughand dyspnea, associated with diffuse patchy interstitial lunginfiltrates on chest X-ray. In the more advanced cases, lungfunction tests show either restrictive or obstructive defects,depending on the extent of alveolar involvement, and hypoxemiawithout CO₂ retention. The diagnosis is often possible on clinicalgrounds, however, in a seriously ill patient uncertainty shouldbe resolved by tissue diagnosis, preferably by open lung biopsy.Treatment is based on symptomatic therapy. The use of corticosteroidsis controversial, but common. Patients with BOOP are exceptional,in that there may be no underlying condition (‘idiopathic’BOOP or cryptogenic organizing pneumonia—COP), a restrictiveventilatory defect is usual and the response to corticosteroidsoften remarkable.     

Toll-like receptor 9 activation: a novel mechanism linking placenta-derived mitochondrial DNA and vascular dysfunction in pre-eclampsia

Emerging evidence suggests that in addition to being the 'power houses' of our cells, mitochondria facilitate effector responses of the immune system. Cell death and injury result in the release of mtDNA (mitochondrial DNA) that acts via TLR9 (Toll-like receptor 9), a pattern recognition receptor of the immune system which detects bacterial and viral DNA but not vertebrate DNA. The ability of mtDNA to activate TLR9?in a similar fashion to bacterial DNA stems from evolutionarily conserved similarities between bacteria and mitochondria. mtDNA may be the trigger of systemic inflammation in pathologies associated with abnormal cell death. PE (pre-eclampsia) is a hypertensive disorder of pregnancy with devastating maternal and fetal consequences. The aetiology of PE is unknown and removal of the placenta is the only effective cure. Placentas from women with PE show exaggerated necrosis of trophoblast cells, and circulating levels of mtDNA are higher in pregnancies with PE. Accordingly, we propose the hypothesis that exaggerated necrosis of trophoblast cells results in the release of mtDNA, which stimulates TLR9 to mount an immune response and to produce systemic maternal inflammation and vascular dysfunction that lead to hypertension and IUGR (intra-uterine growth restriction). The proposed hypothesis implicates mtDNA in the development of PE via activation of the immune system and may have important preventative and therapeutic implications, because circulating mtDNA may be potential markers of early detection of PE, and anti-TLR9 treatments may be promising in the management of the disease.     

A CASE OF SCHISTOSOMAL APPENDICITIS

Acute appendicitis is a great masquerader in surgical practice; its diverse clinical presentation can sometimes lead to delay in diagnosis. Nonetheless, the underlying aetiology of acute appendicitis may not be apparent if the appendix is not sent for histological examination.     

The effect of pes cavus on foot pain and plantar pressure

BACKGROUND: Clinical management of patients with painful pes cavus is challenging because the mechanism of foot pain is poorly understood. The purpose of this study was to explore the influence of various pes cavus aetiologies on foot pain and plantar pressure characteristics, and to identify the relationship between foot pain and plantar pressure. METHODS: Seventy subjects were recruited for this study. They included 30 subjects with pes cavus of unknown aetiology (idiopathic), 10 subjects with pes cavus of neurological aetiology (neurogenic) and 30 subjects with a normal foot type. The presence and location of foot pain was recorded and barefoot plantar pressures were measured using the EMED-SF platform for the whole foot, rearfoot, midfoot and forefoot regions. FINDINGS: Subjects with pes cavus of either idiopathic or neurogenic aetiology reported a higher proportion of foot pain (60%) compared to subjects with a normal foot type (23%) (P=0.009). Pressure-time integrals under the whole foot, rearfoot and forefoot regions in pes cavus, of both idiopathic and neurogenic origin, were higher than in the normal foot type (P<0.01). Pressure-time integrals in subjects reporting foot pain were higher than for pain free subjects (P<0.001). There was a significant correlation between pressure-time integral and foot pain (r=0.49, P<0.001). INTERPRETATION: Foot pain is a common finding among individuals with pes cavus. Regardless of aetiology, pes cavus is characterized by abnormally high pressure-time integrals which are significantly related to foot pain. An understanding of the relationship between pes cavus pressure patterns and foot pain will improve the clinical management of these patients.     

Vomiting and diarrhoea — initial client contact

Vomiting and diarrhoea are two very common presentations in veterinary practice. They may occur together, as seen in gastroenteritis, or may exist independently. It should be remembered, however, that both are clinical signs and not diagnoses. They may be caused by underlying disease or a mechanical abnormality, which may or may not be gastric or intestinal in origin. Both can be caused by a vast number of conditions.     

Pain and Parkinson's disease: Current mechanism and management updates

The aim of this comprehensive review was to provide an overview of pain in Parkinson's disease (PD) by identifying different clinical features and potential mechanisms, and presenting some data on the evaluation and management of pain in PD. PD is a multifocal degenerative and progressive disease, which could affect the pain process at multiple levels. Pain in PD has a multifactorial aetiology, with a dynamic process based on pain intensity, complexity of symptoms, pain pathophysiology and presence of comorbidities. In fact, pain in PD responds to the concept of multimorphic pain, which can evolve, in relation to the different factors, whether they are linked to disease and its management. Understanding the underlying mechanisms will help in guiding of treatment choices. Providing scientific support useful for clinicians and health professionals involved in management of PD, the aim of this review was to bringing practical suggestions and clinical perspectives on the development of a multimodal approach guided by a multidisciplinary clinical intervention through a combination of pharmacological and rehabilitative approaches, to manage pain to improve the quality of life on individuals with PD.     

A clinical overview of endometriosis: a misunderstood disease

Endometriosis is the presence of endometrial glands and stroma outside the endometrial cavity and is the most common known cause of pelvic pain. The number of women being diagnosed with the disease is increasing, but this may be reflective of improved diagnostic techniques. The aetiology is unknown, although the theory of retrograde menstruation remains dominant. Although pain around menstruation is the most frequently experienced symptom, dyspareunia, dyschezia, cyclical dysuria and extreme fatigue are all common. The 'gold standard' diagnostic technique is laparoscopic visualization, and the Royal College of Obstetricians and Gynaecologists (2006) recommends that surgical removal of all endometriotic lesions is the ideal. The experience of endometriosis can negatively affect all aspects of a woman's life and relationships, and this is consistently reported in research studies. This article discusses the aetiology and clinical aspects of endometriosis as well as giving an overview of empirical literature surrounding the experience of the disease. It provides nurses with the knowledge to be alert to the possibility of endometriosis as a diagnosis in women with a certain set of symptoms, in whatever healthcare setting they work.     

Assessment of drug-induced liver injury in clinical practice

Currently, pharmaceutical preparations are serious contributors to liver disease, with hepatotoxicity ranking as the most frequent cause for acute liver failure and post-marketing regulatory decisions. The diagnostic approach of drug-induced liver injury (DILI) is still rudimentary and inaccurate because of the lack of reliable markers for use in general clinical practice. To incriminate any given drug in an episode of liver dysfunction is a step-by-step process that requires a high degree of suspicion, compatible chronology, awareness of the drug's hepatotoxic potential, the exclusion of alternative causes of liver damage, and the ability to detect the presence of subtle data that favour a toxic aetiology. Clinical and laboratory data may also be assessed with algorithms or clinical scales, which may add consistency to the clinical judgment by translating the suspicion into a quantitative score. The CIOMS/RUCAM instrument is considered at present the best method for assessing causality in DILI, although it could be improved through the use of large database of bona fide DILI cases for validation criteria.     

Is the implementation of research findings in the critically ill hampered by the lack of universal definitions of illness?

In the design of clinical trials, a clear definition of disease is essential for enrollment of a homogeneous study population with a higher likelihood of demonstrating a benefit of an intervention. A definition that is applicable to standard clinical practice enhances the ability of clinicians to apply results of the clinical trial to patient care. Use of a universally accepted definition allows valid comparisons across multiple studies. Sepsis, the acute respiratory distress syndrome, and ventilator-associated pneumonia are examples of conditions for which universal definitions developed by panels of experts have facilitated the design of successful clinical trials. However, implementation of the results of some of these studies has been complicated by a lack of understanding or acceptance of disease definitions or by their overly inclusive nature. For example, the presence of Systemic Inflammatory Response Syndrome (SIRS) will identify most patients with sepsis, however, a significant number of patients with those clinical findings will have other underlying processes. Approved definitions for VAP are cumbersome, and adherence to those definitions in the design of clinical trials is poor. This has led to confusion regarding the accuracy of diagnostic tests and poor acceptance of evidence based guidelines by clinicians. When investigators and clinicians do not adhere to common definitions of disease, results of clinical trials may be applied inappropriately or ignored altogether. More specific identifiers of critical illnesses using specific biochemical or genetic markers are being explored. This approach may also be useful for staging disease.     

The use of oral anticoagulants for the treatment of venous thromboembolic events in an ED

Venous thromboembolism (VTE) is a disease spectrum that ranges from deep vein thrombosis (DVT) to pulmonary embolism (PE). Rapid diagnosis and treatment of VTE by emergency care providers are critical for decreasing patient mortality, morbidity, and the incidence of recurrent events. Recent American College of Chest Physicians guidelines recommend initial treatment with unfractionated heparin, low–molecular weight heparin, or fondaparinux overlapped with warfarin for a minimum of 5 days for the treatment of VTE in most cases. Warfarin monotherapy is thereafter continued for 3, 6, or 12 months. These guidelines were published before the approval of target-specific oral anticoagulants (TSOACs), and they have yet to be updated to reflect these new treatment options. For some patients, TSOACs, which act by directly inhibiting factor IIa or factor Xa, may provide safer, more convenient alternatives to warfarin. Their advantages include ease of use, reduced monitoring requirements, and lower bleeding risk than traditional therapy. Additionally, clinical trials have established noninferiority of TSOACs to warfarin for the prevention of recurrent VTE. These trials have demonstrated that TSOACs exhibit similar or lower bleeding rates, particularly intracranial bleeding rates compared with warfarin. Anticoagulation therapy with TSOACs may allow early discharge or outpatient management options for low-risk patients with DVT and PE. This review addresses the importance of early diagnosis and treatment of VTE, outcomes of VTE risk assessment, key efficacy and safety data from phase 3 clinical trials for the various TSOACs for the treatment of DVT and PE, and the corresponding considerations for clinical practice.