The molecular pathogenesis and management of bronchial carcinoids

Introduction: In terms of well-differentiated neuroendocrine tumors (NETs), the lung is the second most common site of occurrence, after the gastro-entero-pancreatic axis, and comprises ～ 25% of all NETs which may occur in various parts of the body. Pulmonary NETs are classified into four groups including typical carcinoid tumors, atypical carcinoid tumors, small cell lung carcinoma and large cell neuroendocrine carcinomas. Among pulmonary NETs, typical and atypical carcinoid tumors of the lung are generally indolent, but do have a (albeit low) potential to metastasize.

Areas covered: The molecular biology and novel molecular pathways and drug targets in bronchial carcinoids are reviewed in this paper. A full data search is performed through PubMed over the years 2000 – 2010 with key words ‘neuroendocrine tumors of the lung, bronchial carcinoid, lung carcinoid, foregut carcinoid, pulmonary carcinoid, pulmonary NETs, lung NETs, molecular biology, autoradiography, nuclear medicine, treatment’; all relevant publications are included, together with selected publications prior to that date.

Expert opinion: Although lying at the benign end of the spectrum of pulmonary NETs, bronchial carcinoids can metastasize, and the pathogenesis of these tumors is poorly understood. Several intracellular signaling pathways are under investigation to define new targets for the successful treatment of these tumors. In terms of treatment, further research should additionally focus on the already known but promising drug options.     

The pathogenesis and management of schizophrenia

Schizophrenia remains a relatively common debilitating and stigmatising disorder, whose precise aetiology is unknown. Research has consistently shown a strong genetic component, although environmental factors are also implicated. A number of biochemical aetiological theories have been proposed but the most plausible is the dopamine hypothesis. This suggests that there is excess activity at central dopaminergic pathways in the brain. Certainly, all effective antipsychotic drugs have dopamine blocking properties. Management of this disorder includes admitting new cases to hospital for careful evaluation by a multidisciplinary team. Although the mainstay of treatment is antipsychotic (neuroleptic) medication, social interventions are also required. These include close liaison with the patient's family, which can help to prevent relapse and aid compliance with drug treatment. Modern therapy aims for recovery of social and occupational skills and gradual rehabilitation back into the community.     

The pathogenesis and medical management of glaucoma

The term glaucoma applies to a group of diseases in which an elevated pressure in the eye causes optic nerve damage resulting in visual loss. Current medical and surgical treatment of glaucoma is designed to lower intraocular pressure to a level at which no further optic nerve damage occurs. This review serves to describe the following aspects of glaucoma and its treatment: aqueous humor dynamics and elevation of intraocular pressure; the pathogenesis of glaucomatous optic nerve damage; the nature of visual loss from glaucoma; the modern medical management of glaucoma; and a discussion of a new drug, forskolin, with potential for clinical use in the treatment of glaucoma.     

支气管哮喘的发病机制及药物治疗研究进展

支气管哮喘是一种慢性炎症引起的以气道高反应性和可逆性阻塞为特点的疾病。近年来随着对其发病机制的深入研究,尤其是对气道慢性炎症机制的全面了解,哮喘的治疗已取得很大进展。目前药物治疗是防治哮喘最有效的方法,应用广泛的药物有糖皮质激素、β2肾上腺素受体激动剂、茶碱类、M胆碱受体阻断药、过敏介质阻释药和抗白三烯药等。新型抗哮喘药物具有疗效好、不良反应少等特点,已成为研究的热点。     

可溶性细胞间黏附分子-1与支气管哮喘病情程度的关系

目的探讨可溶性细胞间黏附分子－1（sICAM－1）与支气管哮喘发作及其病情严重程度的相关性。方法采用ELISA方法测定134例不同时期支气管哮喘患者及健康志愿者血清sICAM-1水平,同时对支气管哮喘急性发作期患者进行肺功能测定。结果63例急性发作期支气管哮喘患者血清sICAM-1[（298．05±52．33）ng／L]水平较缓解期患者[（213．36±16．88）．g／L]及健康志愿者[（117．83±13．23）ng／L]明显升高,并且随哮喘病情加重其值有明显升高;急性发作期患者肺功能第一秒用力呼吸量（FEV．％）值与血清slCAM-1呈明显负相关。结论slCAM-1是支气管哮喘发病中重要的黏附分子,可作为判断病情严重程度的指标之一。     

The vitamin D metabolites in the pathogenesis and management of osteoporosis

Summary

Studies on post-menopausal osteoporotic patients indicate that 1,25-(OH)₂D₃ concentrations are no different from those in age-matched normal subjects and the data suggest that the malabsorption of calcium found in many osteoporotic patients cannot generally be attributed to low plasma 1,25-(OH)₂D₃ levels. The effects are discussed of three different therapies - sex hormones alone, vitamin D metabolites alone and a combination of both - on calcium balance and peripheral bone loss in treated compared with untreated osteoporotic patients. The results indicate that combined therapy with a vitamin D metabolite and an oestrogen is more effective in inhibiting the rate of bone resorption in post-menopausal osteoporosis than treatment with either agent used alone, and should be regarded as the treatment of choice at the present time. It is suggested that, using this regimen which is suitable for patients up to about 65 years of age, calcium supplementation is not required, provided daily calcium intake is reasonably adequate, and may even be undesirable by increasing the risk of hypercalcaemia.     

Pulmonary hypertension: pathogenesis and management

Notable progress has been achieved in our understanding of the pathogenesis of pulmonary hypertension, in particular the role of vasodilators, vasoconstrictors and the intracellular signaling pathways, cytokines, chemokines and growth factors involved. A comprehensive history and clinical examination is mandatory in the assessment and determination of the cause of pulmonary hypertension. This should be complemented by a rationale approach to investigation. Treatment of secondary pulmonary hypertension involves targeting the underlying cause. General measures include oxygen therapy and judicious use of diuretics in patients with overt right heart failure. Newer therapies that have been developed for the treatment of idiopathic pulmonary hypertension include prostanoids, modulators of vascular remodelling such as bosentan and its analogues and PGE-5 inhibitors such as sildenafil. New therapies are likely to become available in the future as our understanding of the pathogenesis of pulmonary hypertension evolves.     

三叉神经痛的分子发病机制的研究进展

三叉神经痛(trigeminal neuralgia,TN)是指三叉神经的一支或几支分布区的反复性、阵发性剧痛,对病人的生活质量影响较大的一种较难完全治愈的疾病,临床一般分为原发性和继发性TN。关于原发性TN的病因和发病机制目前尚不明确。现在,随着分子生物学研究的进展,已经发现多种神经类物质和TN有着密切的联系。该文从分子方面对TN的发病机制研究进展情况作一综述,旨在为TN的治疗提供理论依据。     

Transplacental lung carcinogenesis: molecular mechanisms and pathogenesis

A wide variety of studies in both animal models and human populations have demonstrated age-related differences in the susceptibility of the developing organism to environmentally prevalent toxicants. While this differential susceptibility has been clearly established, the mechanistic basis for these age-related differences is still poorly understood. The developing fetus utilizes many of the same metabolic and signaling pathways as adult organisms in responding to environmental agents. However, it is becoming increasingly evident that the fetus is not a "little adult" and exhibits unique biochemical responses and gene expression profiles to chemical and physical agents. Because of the rapid growth and developmental changes that occur during gestation, the fetus represents a particularly challenging research subject as a result of the dynamic alterations that occur in gene expression pathways as gene systems are activated or repressed during specific stages of development. Thus, an understanding of the mechanism(s) that render the developing organism more or less susceptible to specific carcinogenic agents is crucial for both regulatory decisions regarding the determination of safe levels of toxic chemicals released into the environment and also for determining the effects of therapeutic compounds in younger age groups and pregnant women. Concentrating on studies from the author's laboratory, this review will highlight recent research on the molecular pathogenesis of transplacentally induced tumors. While focusing on the lung, other animal models and recent human epidemiological studies will also be discussed to contrast similarities and differences in the developing and adult organisms in terms of responses to toxic chemicals, including metabolism of environmentally prevalent toxicants and alterations in gene systems at the molecular level.     

Adrenoleukodystrophy: molecular pathogenesis and development of therapeutic agents

Adrenoleukodystrophy (ALD) is an inherited disorder characterized by progressive demyelination of the central nervous system and adrenal dysfunction. The biochemical characterization is made based on the accumulation of pathognomonic amounts of saturated very long chain fatty acid (VLCFA, >22) in all tissues, including brain white matter and adrenal glands. The accumulation of VLCFA is linked to a mutation in the ABCD1 gene that encodes ABCD1/ALDP, a peroxisomal ABC protein. ABCD1/ALDP is thought to be involved in the active ATP-driven transport of VLCFA-CoA from the cytoplasm into the peroxisomes. However, the precise function of ABCD1/ALDP is still unclear. The accumulation of VLCFA is caused by reducing peroxisomal VLCFA beta-oxidation and/or increasing fatty acid elongation. Since the reduction of accumulated VLCFA in the brain is thought to be crucial for preventing the progression of neurologic symptoms in X-ALD, compounds that can cross the blood-brain barrier and decrease the VLCFA levels in the brain would be a highly attractive candidate for effective treatment of ALD patients. We found that baicalein 5,6,7-trimethyl ether, a flavonoid derivative, decreased the VLCFA level in X-ALD fibroblasts, possibly by activating peroxisomal fatty acid beta-oxidation. Continued pharmacologic studies of flavonoids and chemically modified derivatives may lead to major advances in the pharmacologic therapy for X-ALD.     

Drug-induced hypertension: pathogenesis and management.

Estrogenic compounds are the most important group of drugs that can induce hypertension. Studies have shown an incidence of significant hypertension amounting to less than 1% after 1 year of taking oral contraceptives and about 2% after 5 years. The ratio of the incidence of hypertension among 'takers' to that of 'nontakers' has been assessed at 1.8 by 1 study and 2.6 by another. Small but significant increments in systolic and diastolic pressures can be discerned during the first 2 years of treatment. Cessation of treatment has resulted in pressures returing to pretreatment levels within 3 months. In those previously normal the highest readings during oral contraceptive use were only 155/90 mm of Hg. Severe hypertension is more likely to occur in the predisposed, and malignant hypertension has been reported. Previous hypertension, toxemia of pregnancy, obesity, and nephropathy are predisposing conditions. Although progestagens, used alone, do not cause clinical hypertension the incidence of hypertension associated with an estrogen-progestogen combination was directly related to the dose of progestagen used. Weight gain is often observed in oral contraceptive users and is occasionally accompanied by edema and hypertension. There is a marked increase in the circulating level of renin substrate (angiotensinogen) which is caused by the estrogen component of the pill. The increase in renin substrate is associated with increase in plasma levels of renin activity, angiotensin 2, and aldosterone, together with a fall in plasma renin concentration. The suppression of plasma renin concentration can persist for weeks after stopping the pill. The factors responsible for hypertension are probably intrinsic and may be either neural, vascular, or renal. Patients taking oral contraceptives should have blood pressure checks at 6-month intervals, and more frequently in high risk cases. In the management of those with only mild blood pressure elevation, such patients should change to a preparation with the lowest available estrogen dosage, 30 mcg of ethinyl estradiol, or reserve the method for use during crucial periods of family planning. With moderate hypertension the oral contraceptive should be suspended for 3-6 months. If the blood pressure falls, oral contraceptives should not be resumed but another method recommended. Continuing hypertension requires further study and possibly elective sterilization. Severe hypertension requires withdrawal of the pill, urgent investigation, and treatment. Other drugs may cause hypertension. Management of these patients is outlined. Structural formulae of progesterone, norethisterone acetate, medroxyprogesterone acetate, and norgestrel are shown.     

Signal transduction of IL-13 and its role in the pathogenesis of bronchial asthma

Interleukin-13 (IL-13) is a Th2-type cytokine, secreted from CD4(+) T cells, mast cells, basophils and eosinophils. The human IL-13 gene locates at 5q31, generating a cluster with other Th2-type cytokines such as IL-4 and IL-5. Although the homology between IL-13 and IL-4 at the amino acid level is only about 25%, the IL-13 structure determined by NMR is very similar to that of IL-4. Both cytokines share their receptors and signal pathways, giving these two cytokines similar biological properties. However, the important role of IL-13 in the pathogenesis of bronchial asthma has recently been recognized, based mainly on analyses of mouse models. IL-13 and its signal pathway are thought to be promising targets to develop a therapeutic reagent for bronchial asthma. In this article, we summarize the signal transduction pathway of IL-13, the pathological roles of IL-13 in bronchial asthma and the reagents to inhibit IL-13 signals that are now under development.     

Eosinophilic oesophagitis: epidemiology, pathogenesis and management

Eosinophilic oesophagitis (EE) is a clinico-pathological entity recognized with increased frequency in children and adults. It is an atopic disease involving ingested and inhaled allergens. A pathological eosinophilic infiltrate is diagnosed by finding ≥ 15 eosinophils per high-powered field on oesophageal mucosal biopsies. This infiltrate may result in a narrowed oesophageal lumen. It does not involve the stomach or duodenum. Children commonly present with abdominal pain, vomiting and dysphagia. Presentation in adults is with dysphagia, heartburn, chest pain or impaction of a food bolus in the oesophagus. There is often a history of allergy (asthma, hay fever, eczema). A male predominance (70% in adults) is unexplained. Distinctive endoscopic features are linear furrows, mucosal rings and white papules, and the narrowed lumen may be appreciated. Although EE and gastro-oesophageal reflux disease are separate entities, there is a significant overlap of the conditions. Treatment options include nonpharmacological approaches including an elimination or elemental diet, and/ or medications, chiefly with corticosteroids. The topical administration of fluticasone propionate has been demonstrated to improve symptoms and mobilize the pathological infiltrate of eosinophils. There has been a variable effect with the leukotriene receptor antagonist montelukast and promising early results with mepolizumab, a monoclonal antibody against interleukin-5. The long-term efficacy of topical corticosteroids has not been well studied and most patients experience recurrent symptoms when treatment is completed. Currently, repeated short courses of topical corticosteroids are utilized. Acid suppression by a proton pump inhibitor may be considered in view of the overlap between EE and gastro-oesophageal reflux disease.     

Allergic fungal sinusitis: pathogenesis and management strategies

Allergic fungal sinusitis (AFS) is a noninvasive form of highly recurrent chronic allergic hypertrophic rhinosinusitis that can be distinguished clinically, histopathologically and prognostically from the other forms of chronic fungal rhinosinusitis. There are three invasive (acute necrotising, chronic invasive and granulomatous invasive) and two noninvasive (fungal ball and allergic fungal) forms of fungal rhinosinusitis currently recognised. Confusion in differentiating between the various forms of fungal rhinosinusitis and between other forms of chronic hypertrophic sinus disease (HSD) can be eliminated by adhering to strict diagnostic criteria. Although there are characteristic presenting clinical history and physical examination findings, laboratory test results, including elevated total serum IgE and positive inhalant allergy skin tests, and sinus computed tomography scans showing chronic rhinosinusitis (often with the presence of hyperattenuating sinus contents) diagnosis of AFS is essentially based on histopathology obtained from sinus surgery. Histopathology shows the presence of eosinophilic-lymphocytic sinus mucosal inflammation, extramucosal allergic mucin (that is also seen grossly at surgery as a characteristic 'peanut-buttery' material), and scattered silver stain positive fungal hyphae within the allergic mucin but not in the mucosa. Treatment and follow up of AFS has been based on its immunopathological analogy to allergic bronchopulmonary aspergillosis, a similar noninvasive fungal hypersensitivity disorder of the lung, and its clinical and pathophysiological relationship to other forms of HSD and asthma. Treatment involves aggressive sinus surgery followed by medical management that includes allergen immunotherapy, topical and systemic corticosteroids, antihistamines and antileukotrienes. Total serum IgE levels should be followed postoperatively as they can be prognostic for recurrent disease. Close follow up and coordination of treatment by both medical and surgical physicians as a team leads to the best clinical outcomes. Ongoing studies are being directed at furthering our understanding of the pathophysiological relationships and treatment options for AFS, and other common forms of chronic hypertrophic rhinosinusitis disorders.     

Hashimoto's encephalopathy : epidemiology, pathogenesis and management

Hashimoto's encephalopathy is a term used to describe an encephalopathy of presumed autoimmune origin characterised by high titres of antithyroid peroxidase antibodies. In a similar fashion to autoimmune thyroid disease, Hashimoto's encephalopathy is more common in women than in men. It has been reported in paediatric, adult and elderly populations throughout the world. The clinical presentation may involve a relapsing and remitting course and include seizures, stroke-like episodes, cognitive decline, neuropsychiatric symptoms and myoclonus. Thyroid function is usually clinically and biochemically normal.Hashimoto's encephalopathy appears to be a rare disorder, but, as it is responsive to treatment with corticosteroids, it must be considered in cases of 'investigation negative encephalopathies'. Diagnosis is made in the first instance by excluding other toxic, metabolic and infectious causes of encephalopathy with neuroimaging and CSF examination. Neuroimaging findings are often not helpful in clarifying the diagnosis. Common differential diagnoses when these conditions are excluded are Creutzfeldt-Jakob disease, rapidly progressive dementias, and paraneoplastic and nonparaneoplastic limbic encephalitis. In the context of the typical clinical picture, high titres of antithyroid antibodies, in particular antithyroid peroxidase antibodies, are diagnostic. These antibodies, however, can be detected in elevated titres in the healthy general population. Treatment with corticosteroids is almost always successful, although relapse may occur if this treatment is ceased abruptly. Other forms of immunomodulation, such as intravenous immune-globulin and plasma exchange, may also be effective.Despite the link to autoimmune thyroid disease, the aetiology of Hashimoto's encephalopathy is unknown. It is likely that antithyroid antibodies are not pathogenic, but titres can be a marker of treatment response. Pathological findings can suggest an inflammatory process, but features of a severe vasculitis are often absent. The links between the clinical pictures, thyroid disease, auto-antibody pattern and brain pathology await further clarification through research. It may be that Hashimoto's encephalopathy will be subsumed into a group of nonvasculitic autoimmune inflammatory meningoencephalopathies. This group may include disorders such as limbic encephalitis associated with voltage-gated potassium channel antibodies. Some authors have suggested abandoning any link to Hashimoto and renaming the condition 'steroid responsive encephalopathy associated with autoimmune thyroiditis' to better reflect current, if limited, understanding of this condition.     

Clinical features, pathogenesis and management of drug-induced seizures

Many classes of pharmacological agents have been implicated in cases of drug-induced seizures. The list includes antidepressant drugs, lithium salts, neuroleptics, antihistamines (H1-receptor antagonists), anticonvulsants, central nervous system stimulants, general and local anaesthetics, antiarrhythmic drugs, narcotic and non-narcotic analgesics, non-steroidal anti-inflammatory drugs, antimicrobial agents, antifungal agents, antimalarial drugs, antineoplastic drugs, immunosuppressive drugs, radiological contrast agents and vaccines. For each of these classes of drugs, this article offers a revision of the literature and emphasises in particular the frequency of the adverse reaction, its clinical presentation, its presumed epileptogenic mechanism and the therapeutic strategy for the management of drug-induced seizures. An attempt is also made to distinguish seizures induced by standard dosages from those provoked by accidental or self-induced intoxication. For some classes of drugs such as antidepressants, neuroleptics, central nervous system stimulants (e.g. theophylline, cocaine, amphetamines) and beta-lactam antibiotics, seizures are a well recognised adverse reaction, and a large body of literature has been published discussing exhaustively the major aspects of the issue; sufficient data are available also for the other classes of pharmacological agents mentioned above. In contrast, several other drugs [e.g. allopurinol, digoxin, cimetidine, protirelin (thyrotrophin releasing hormone), bromocriptine, domperidone, insulin, fenformin, penicillamine, probenecid, verapamil, methyldopa] have not been studied thoroughly under this aspect, and the only source of information is the occasional case report. This review does not address the issue of seizures induced by drug withdrawal.     

父母认知及管理对支气管哮喘患儿治疗效果的影响

目的将父母认知及管理应用于支气管哮喘患儿临床治疗中,对其临床效果讨论研究。方法参与本实验的支气管患儿共100例,按照随机数字表法将所有患儿分成研究组和对照组,其中对照组患儿接受传统常规临床护理,研究组患儿接受父母认知管理,对两组患儿相关临床指标数据变化情况进行比较分析。结果相比于对照组患儿的临床治疗依从性和总有效率76%(38/50)和78%(39/50)而言,研究组患儿临床治疗依从性96%(48/50)和临床治疗总有效率98%(49/50)均更高;同时治疗后相比于对照组患儿日间和夜间哮喘评分(1.75±0.53)、(1.70±0.43)分而言,研究组患儿日间和夜间哮喘评分(0.46±0.13)、(0.54±0.12)分均更低(P<0.05)。结论将父母认知及管理应用于支气管哮喘患儿临床治疗中,能够进一步改善患儿的哮喘情况,这对于促进患儿身体恢复、提高了临床治疗效果具有重要意义。