Future therapeutic options for celiac disease

Celiac disease is a disorder of the small intestine caused by an inappropriate immune response to wheat gluten and similar proteins of barley and rye. At present, the only available treatment is a strict gluten-exclusion diet; hence the need for alternative treatments. Recent advances have improved our understanding of the molecular basis for this disorder and there are several attractive targets for new treatments. Oral enzyme supplementation is designed to accelerate gastrointestinal degradation of proline-rich gluten, especially its proteolytically stable antigenic peptides. Complementary strategies aiming to interfere with activation of gluten-reactive T cells include the inhibition of intestinal tissue transglutaminase activity to prevent selective deamidation of gluten peptides, and blocking the binding of gluten peptides to the HLA-DQ2 or HLA-DQ8 molecules. Other possible treatments include cytokine therapy, and selective adhesion molecule inhibitors that interfere with inflammatory reactions, some of which are already showing promise in the clinic for other gastrointestinal diseases.     

Physical activity in statin-treated patients

Physical inactivity is increasing in virtually all developed and developing countries and is estimated to cause 2 million deaths worldwide annually. Conversely, regular exercise contributes to the primary and secondary prevention of cardiovascular disease, improves wellness, attenuates age-related decline and reduces risk of premature death. However, it is widely believed that lifestyle interventions are difficult to institute and difficult to maintain and drugs, particularly statins, should be considered as the fundamental tool in the prevention of coronary artery disease. It is therefore a concern that statins may adversely affect the muscle's ability to appropriately respond to physical exertion. Statin therapy can induce skeletal muscle damage in treated patients, despite their being asymptomatic and without increment of serum creatine kinase level. In clinical practice, muscle complaints due to statin therapy are easily dismissed by the patient and physician. Such muscle effects are likely related to mitochondrial dysfunction and may well affect 25% of statin users who exercise and thus constitute one of the most common and underappreciated side effects of statins. Physical activity is affordable to all, as opposed to statins, and should be regarded as one of the most cost-effective ways to prevent cardiovascular disease. Physicians should be aware that statins may interfere with patient's activity levels.     

Prevalence and risk distribution of residual dyslipidemia in statin-treated patients in Greece

Many statin-treated patients are not achieving treatment goals and are at risk of cardiovascular (CV) disease. We report the results of patients enrolled in an observational study in Greece, which estimated the residual lipid abnormalities in statin-treated patients. Low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), and triglyceride concentrations were recorded in patients receiving statin therapy for ≥ 3 months, classified by CV risk according to European Society of Cardiology guidelines. Sixty-three percent of statin-treated patients had an LDL-c not at goal. Low-risk patients were more likely to have an LDL-c not at goal compared with high-risk patients (67.3% vs 61.0%, respectively). They were also less likely to have low HDL-c levels and elevated triglyceride levels compared with high-risk patients. Smoking and sedentary lifestyle were not associated with dyslipidemia in this population. Approximately two thirds of statin-treated patients in Greece are not reaching target/normal lipid levels and could benefit from improved lipid management.     

Pulmonary infections in ventilated patients: Diagnostic and therapeutic options

The diagnosis of pulmonary infections in the ventilated patient has threatened the foundations of medicine. Although the lifesaving techniques of endotracheal intubation (developed for the treatment of diphtheria) and artificial ventilation (developed for the management of poliomyelitis) contribute greatly to medical care, they have resulted in the production of the “progress”-related infection of ventilator-associated pneumonia (VAP). Modern ventilator therapy is a substantial technologic advance from earlier days and, as technology inherently does, has removed some of the human element, the main foundation of Oslerian medical practice. The time-honored clinical diagnosis based on physical examination by an experienced physician has been seriously compromised in the approach to VAP.     

Diabesity: therapeutic options

A pathogenic relationship exists between type 2 diabetes and obesity. Over the last decade, the escalation in diabetes cases has paralleled the rapid increase in obesity rates, constituting a global health crisis. Environmental risk factors attributed to the global increase in obesity include the consumption of high‐calorie, high‐fat foods and inadequate physical activity. Obese individuals may also have a genetic predisposition for obesity. Both diabetes and obesity confer an elevated risk of developing a range of complications and comorbidities, including cardiovascular disease, hypertension and stroke, which can complicate disease management. This review examines the aetiology of the linkages between diabetes and obesity and the range of available therapies. Recent clinical evidence substantiating the efficacy and safety of incretin‐based antidiabetic therapies is analysed, in addition to data on antiobesity therapeutic strategies, such as antiobesity agents, behaviour modification and bariatric surgery. Glucose control is often accompanied by weight‐neutral or modest weight reduction effects with DPP‐4 inhibitor treatment (sitagliptin, vildagliptin, saxagliptin) and weight loss with GLP‐1 receptor agonist therapy (exenatide, liraglutide). Studies of antiobesity agents including orlistat, sibutramine and rimonabant have shown attrition rates of 30–40%, and the long‐term effects of these agents remain unknown. Bariatric surgical procedures commonly performed are laparoscopic adjustable banding of the stomach and the Roux‐en‐Y gastric bypass, and have produced type 2 diabetes remission rates of up to 73%. Therapeutic strategies that integrate glycaemic control and weight loss will assume greater importance as the prevalence of diabetes and obesity increase.     

Contemporary therapeutic options for children with high risk neuroblastoma

Despite the use of aggressive chemotherapy, stage 4 high risk neuroblastoma still has a very poor prognosis, which is estimated at 25%. Therefore, novel treatment approaches are needed. Increasing number of reports has been concerned with the use of novel treatment modalities. Literature regarding intensive induction, local therapy, myeloablative therapy and immunotherapy and biotherapy was reviewed in order to draw conclusions and recommendations for the management of children with high risk neuroblastic tumors.     

Homocysteine, endothelial dysfunction and cardiovascular risk: pathomechanisms and therapeutic options

Elevated homocyst(e)ine plasma concentrations are an independent risk factor for cardiovascular disease. Hyperhomocyst(e)inaemia is common in patients with peripheral arterial occlusive disease, coronary heart disease, cerebrovascular disease, carotid artery stenosis and venous thromboembolism. Endothelial dysfunction may be one underlying cause leading to proatherogenic effects associated with hyperhomocyst(e)inaemia. However, the mechanisms which lead to impaired endothelial function in hyperhomocyst(e)inaemia are not fully understood. Recent evidence suggests that homocyst(e)ine may interact with physiological mediators of the endothelial matrix. Oxidative mechanisms and decreased biological activity of endothelium-derived nitric oxide (NO) may also contribute to homocyst(e)ine-associated endothelial dysfunction. B vitamins are essential cofactors in the metabolism of homocyst(e)ine to methionine via the remethylation-pathway (vitamin B12, folic acid) and to cystathionine via the transsulphuration-pathway (vitamin B6). Dietary deficiencies of folic acid, vitamin B12, and vitamin B6 appear to be common among elderly people in the western world and represent one pathogenic factor related to the incidence of hyperhomocyst(e)inaemia. Several studies have demonstrated that dietary supplementation with folic acid and the vitamins B12 and B6 is an efficient means to decrease plasma homocyst(e)ine. No clinical studies are available to date to prove whether reducing homocyst(e)ine levels to the normal range by supplementary B vitamins will also beneficially affect vascular function or cardiovascular risk. Furthermore it is unknown whether moderately elevated homocyst(e)ine concentrations per se may predispose to development of vascular disease, or whether homocyst(e)ine is an indirect marker of cardiovascular disease. Further investigations will be necessary to elucidate the causal relationship between elevated homocyst(e)ine plasma concentrations and the incidence of cardiovascular events, especially since the therapeutic strategies in hyperhomocyst(e)inaemia would differ depending on the underlying pathophysiological mechanisms.     

Management of coronary artery disease: therapeutic options in patients with diabetes

OBJECTIVES: The aim of this review is to discuss the particularities of coronary artery disease (CAD), the effect of intensive medical management and the outcome of percutaneous and surgical revascularization in patients with diabetes mellitus (DM). BACKGROUND: CAD represents the leading cause of death in patients with DM. Numerous clinical, biological and angiographic risk factors have been shown to be associated with CAD in diabetic patients. METHODS: Metabolic abnormalities in patients with DM including insulin resistance, hyperglycemia and dyslipidemia are briefly discussed. Then the potential roles of medical management and of percutaneous and surgical coronary revascularization are more extensively reviewed. RESULTS: More vigorous control of hyperglycemia, hyperlipidemia, hypertension and other risk factors may be of crucial importance for risk reduction. Despite remarkable progress in recent years, the choice of a coronary revascularization strategy remains a challenge in these patients. Diabetic patients with CAD are predisposed to higher cardiovascular events after balloon angioplasty. Whether stenting and new antiplatelet drugs improve the results of percutaneous revascularization in this population needs further evaluation. The superiority of the surgical approach is also not definitely established. Therefore, many aspects of coronary revascularization are still unclear in these patients. CONCLUSIONS: The results of ongoing randomized trials comparing multiple coronary stents to bypass surgery will likely provide some answers to our questions and additional randomized trials evaluating intensive diabetic control with or without coronary revascularization are needed to determine the best therapeutic approach in these patients.     

Patent foramen ovale: pathophysiology and therapeutic options in symptomatic patients.

The foramen ovale, a remnant from the fetal circulation, remains patent through adulthood in approximately 1/4th of the general population, thus representing the most common persistent abnormality of fetal origin. In these individuals, the patent foramen ovale (PFO) permits interatrial right-to-left shunting during those periods of time when right atrial exceeds left atrial pressure. Recently, the pathophysiological aspects of the PFO have been increasingly appreciated, giving rise to disease manifestations such as paradoxical embolism, refractory hypoxemia in patients with right ventricular infarction or severe pulmonary disease, orthostatic desaturation in the setting of the rare platypnea-orthodeoxia syndrome, neurological decompression illness in divers, and migraine headache with aura. Despite the growing recognition of the PFO, particularly when associated with an atrial septal aneurysm, as risk factor for paradoxical embolism, the optimal treatment strategy for symptomatic patients remains undefined. Most patients with presumed paradoxical embolism are currently treated medically with antithrombotic medications, with a paucity of data concerning the efficacy of oral anticoagulant as opposed to antiplatelet therapy. Surgical PFO closure has proved feasible, but the procedure is associated with the well known complications of cardiac surgery, and the results have been mixed with respect to stroke prevention. The recent introduction of interatrial septal occlusion devices set the stage for a minimally invasive, percutaneous approach. The present article discusses the pathophysiology of the PFO, and the advantages and drawbacks of the different therapeutic options available for symptomatic patients.     

Managing the residual cardiovascular disease risk associated with HDL-cholesterol and triglycerides in statin-treated patients: A clinical update

Cardiovascular disease (CVD) is a significant cause of death in Europe. In addition to patients with proven CVD, those with type 2 diabetes (T2D) are at a particularly high-risk of CVD and associated mortality. Treatment for dyslipidaemia, a principal risk factor for CVD, remains a healthcare priority; evidence supports the reduction of low-density lipoprotein cholesterol (LDL-C) as the primary objective of dyslipidaemia management.While statins are the treatment of choice for lowering LDL-C in the majority of patients, including those with T2D, many patients retain a high CVD risk despite achieving the recommended LDL-C targets with statins. This ‘residual risk’ is mainly due to elevated triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) levels. Following statin therapy optimisation additional pharmacotherapy should be considered as part of a multifaceted approach to risk reduction. Fibrates (especially fenofibrate) are the principal agents recommended for add-on therapy to treat elevated TG or low HDL-C levels. Currently, the strongest evidence of benefit is for the addition of fenofibrate to statin treatment in high-risk patients with T2D and dyslipidaemia. An alternative approach is the addition of agents to reduce LDL-C beyond the levels attainable with statin monotherapy.Here, addition of fibrates and niacin to statin therapy is discussed, and novel approaches being developed for HDL-C and TG management, including cholesteryl ester transfer protein inhibitors, Apo A-1 analogues, mipomersen, lomitapide and monoclonal antibodies against PCSK9, are reviewed.     

Mini-review: new therapeutic options in hypoparathyroidism

Hypoparathyroidism is a disorder characterized by hypocalcemia and low or absent parathyroid hormone (PTH). While standard treatment of hypoparathyroidism consists of oral calcium and vitamin D supplementation, maintaining serum calcium levels can be a challenge, and concerns exist regarding hypercalciuria and ectopic calcifications that can be associated with such treatment. Hypoparathyroidism is the only classic endocrine deficiency disease for which the missing hormone, PTH, is not yet an approved treatment. This mini-review focuses on the use of PTH in the treatment of hypoparathyroidism. There are two available formulations of PTH: teriparatide [human PTH(1-34)] and the full-length molecule, PTH(1-84). Both PTH(1-34) and PTH(1-84) lower supplemental vitamin D requirements and increase markers of bone turnover. Densitometric and histomorphometric studies in some subjects treated with PTH(1-84) demonstrate improvement in abnormal bone-remodeling dynamics and return of bone metabolism toward normal euparathyroid levels. Further detailed examination of skeletal features following therapy with the different treatment regimens and data regarding the effect of PTH on quality of life measures are under active investigation.     

Cellular transplantation: future therapeutic options

PURPOSE OF REVIEW: Cardiac transplantation is a complex undertaking and an imperfect solution to end-stage heart failure. Cellular transplantation has been proposed as an alternative solution; however, clinical trials at present are small and show variable results. The mechanisms behind stem cell therapy have not yet been elucidated. RECENT FINDINGS: Several large trials have been presented that address the question of bone marrow stem cells as therapy for acute myocardial infarction, and also the possible benefits of therapy with granulocyte colony-stimulating factor. Although some trials show a modest improvement in ejection fraction or reduction of infarct size, other trials show no change with treatment. Fewer clinical data are available on the treatment of chronic left ventricular systolic function. Many questions remain such as what cell type to use, dosing, the ideal timing for therapy, and the technique of cell delivery. Finally, further research continues on the cellular milieu, enhancement of cell engraftment, proliferation, and survival. SUMMARY: This review briefly examines the background for stem cell therapy, as well as the larger clinical trials of stem cell therapy for acute myocardial infarction and chronic left ventricular systolic dysfunction, and possible pharmacologic enhancement options.     

Improving therapeutic options for patients with giant cell arteritis

PURPOSE OF REVIEW: Glucocorticoids remain the mainstay of treatment of giant cell arteritis. The aim of this review is to establish the optimal schedule of glucocorticoid administration, and to ascertain which other treatments may be used as glucocorticoid-sparing agents. RECENT FINDINGS: An initial dose of 40-60 mg/day of prednisone is usually adequate. Patients at risk of developing ischemic complications require dosages of around 1 mg/kg/day, whereas pulse glucocorticoid therapy is no more effective in preventing ischemic complications. In patients with longstanding disease or those at risk for glucocorticoid-related adverse events, methotrexate or azathioprine can be used as glucocorticoid-sparing drugs. Infliximab has been demonstrated to be efficacious in glucocorticoid-resistant disease in an open study, whereas a randomized controlled trial showed no efficacy in patients with recent-onset disease. Finally, two retrospective studies suggest that low-dose aspirin may decrease the rate of cranial ischemic complications secondary to giant cell arteritis. SUMMARY: Glucocorticoids remain the cornerstone of therapy for giant cell arteritis. To achieve maximal efficacy but minimize glucocorticoid-related adverse reactions, dosage should be individually tailored. In patients with longstanding, recalcitrant disease, methotrexate, azathioprine or tumor necrosis factor-alpha inhibitors may be considered. Aspirin is recommended in all patients unless contraindicated. Osteoporosis prophylaxis should also be regularly implemented.     

Typhoid fever: narrowing therapeutic options in India

Typhoid fever remains an important public health problem in India. One thousand four hundred fifty-eight blood cultures were screened, 178 grew out Salmonella enterica serovar Typhi. On agar dilution minimum inhibitory concentration (MIC) testing, 0.6% of the isolates were resistant to ciprofloxacin, 2% to cefotaxime and 1% to cefepime. Nalidixic acid resistance was observed in 51% isolates, of which 98.9% had decreased susceptibility (MIC > or = 0.125-4 microg/ml) to ciprofloxacin. One strain of nalidixic acid sensitive S. Typhi (NASST) also had a decreased MIC (0.125 microg/ml) to ciprofloxacin. Resistance to third and fourth generation cephalosporins is emerging in India and will gain significance in the coming decade. The molecular basis of resistance to cephalosporinsand ciprofloxacin resistance in NASST strains need to be further evaluated for S. Typhi.     

拓宽支气管哮喘的治疗

支气管哮喘（简称哮喘）是一种气道的慢性炎症性疾病。多数哮喘患者对吸人糖皮质激素（ICS）高度有效，使ICS成为哮喘的一线控制药物。但是，仍有相当数量的哮喘患者对ICS治疗反应较差，这部分患者被称为难治性哮喘。对于这部分哮喘患者国内外近几年出现了一些新的治疗药物和方法，本文对这一新的治疗动向进行综述。     

Emerging therapeutic options in GERD

Gastroesophageal reflux disease (GERD) is a prevalent problem resulting in a high level of healthcare consultation and expenditure in the Western World. Although standard medical therapy (in the form of proton pump inhibitor drugs) is effective in the majority of cases, there remains a significant proportion who are refractory to treatment. In addition, surgical therapy (in the form of laparoscopic fundoplication) is not always effective, and in some can be associated with significant side-effects, particularly gas-bloat, flatulence and dysphagia.As such there remains an unmet need in GERD to develop new therapies for refractory cases, and to develop alternatives to fundoplication with fewer side-effects.This article discusses the current state of pharmacological and non-pharmacological emerging therapies for GERD.     

Hypertension and diabetes: new therapeutic options

The treatment of high-risk hypertensive patients with diabetes presents clinicians with challenges and opportunities. The coexistence of hypertension and diabetes dramatically and synergistically increases the risk of microvascular and macrovascular complications. Perhaps most important among these is the increased risk of cardiovascular events in this patient population, an observation that can be best appreciated by the increased number of deaths attributed to cardiovascular-related diseases in diabetic patients aged 45 to 65 years. Consequently, aggressive therapy in this population offers the promise of significantly reducing excess cardiovascular deaths. Despite this opportunity for reducing mortality in these high-risk patients, several challenges to treatment remain. While aggressive blood pressure reduction has been documented to reduce the rate of events in these patients, questions remain as to the level to which blood pressure should be reduced. The recent guidelines from the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure emphasized the importance of treating patients with hypertension and diabetes as if they already have target organ damage. Low blood pressure targets of 130/85 mm Hg, with an optimal goal of 120/80 mm Hg, can reduce the risk of events in hypertensive patients with diabetes, regardless of the pharmacological means used. However, there are physiologic and clinical rationale for renin angiotensin system blockade, with angiotensin-converting enzyme inhibition as the preferential therapy in these patients. In this regard, preliminary data with the new class of angiotensin II receptor blockers suggest that these agents may offer benefits equivalent to those observed with angiotensin-converting enzyme inhibitors while offering better tolerance.     

Prehypertension: Underlying pathology and therapeutic options

Prehypertension(PHTN) is a global major health risk that subjects individuals to double the risk of cardiovascular disease(CVD) independent of progression to overt hypertension. Its prevalence rate varies considerably from country to country ranging between 21.9% and 52%. Many hypotheses are proposed to explain the underlying pathophysiology of PHTN. The most notable of these implicate the renin-angiotensin system(RAS) and vascular endothelium. However, other processes that involve reactive oxygen species, the inflammatory cytokines, prostglandins and C-reactive protein as well as the autonomic and central nervous systems are also suggested. Drugs affecting RAS have been shown to produce beneficial effects in prehypertensives though such was not unequivocal. On the other hand, drugs such as β-adrenoceptor blocking agents were not shown to be useful. Leading clinical guidelines suggest using dietary and lifestyle modifications as a first line interventional strategy to curb the progress of PHTN; however, other clinically respected views call for using drugs. This review provides an overview of the poten-tial pathophysiological processes associated with PHTN, abridges current intervention strategies and suggests investigating the value of using the "Polypill" in prehypertensive subjects to ascertain its potential in delaying(or preventing) CVD associated with raised blood pressure in the presence of other risk factors.     

Inappropriate sinus tachycardia: current therapeutic options

Inappropriate sinus tachycardia (IST) is an uncommon form of arrhythmia characterized by an increased heart rate that is out of proportion to a normal physiologic demand. The etiology of IST remains ill-defined and controversial. Clinical presentation of IST is highly variable, from isolated to sustained palpitations, and can cause deterioration in one's quality of life. IST is usually a diagnosis of exclusion and it is important to rule out other causes of sinus tachycardia before reaching a final diagnosis. Evaluation of cardiac autonomic reflex function is essential to support the diagnosis of IST. The treatment of IST aims to target the multiple mechanisms involved in this disease, and multidisciplinary management, including cardiac rehabilitation, pharmacotherapy, and occasionally radiofrequency modification of the sinus node, should be considered. The prognosis is usually benign, although regular follow-up is required to optimize therapy and prevent the onset of tachycardiomyopathy.