May 2015, Volume 9 Issue 2

Cover illustration

  • Transbronchial lung biopsy exhibited dilated alveolar spaces with laminated calcific concretions. Our final diagnosis was pulmonary alveolar microlithiasis with associated bronchial asthma. (Courtesy of Dr. Nidhya Ganesan. See pages 229-238 by Nidhya Ganesan et al. for more information.)

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    Weiping Jia
    Peter B. Alexander,Xiao-Fan Wang

    Drug resistance is a major factor that limits the efficacy of targeted cancer therapies. In this review, we discuss the main known mechanisms of resistance to receptor tyrosine kinase inhibitors, which are the most prevalent class of targeted therapeutic agent in current clinical use. Here we focus on bypass track resistance, which involves the activation of alternate signaling molecules by tumor cells to bypass inhibition and maintain signaling output, and consider the problems of signaling pathway redundancy and how the activation of different receptor tyrosine kinases translates into intracellular signal transduction in different cancer types. This information is presented in the context of research strategies for the discovery of new targets for pharmacological intervention, with the goal of overcoming resistance in order to improve patient outcomes.

    Jianping Ye

    In obesity, chronic inflammation is believed to induce insulin resistance and impairs adipose tissue function. Although this view is supported by a large body of literature, it has been challenged by growing evidence that pro-inflammatory cytokines may favor insulin sensitivity through induction of energy expenditure. In this review article, interleukin 15 (IL-15) is used as a new example to explain the beneficial effects of the pro-inflammatory cytokines. IL-15 is secreted by multiple types of cells including macrophages, neutrophils and skeletal muscle cells. IL-15 expression is induced in immune cells by endotoxin and in muscle cells by physical exercise. Its transcription is induced by transcription factor NF-κB. IL-15 binds to its receptor that contains three different subunits (α, β and γ) to activate JAK/STAT, PI3K/Akt, IKK/NF-κB and JNK/AP1 pathways in cells. In the regulation of metabolism, IL-15 reduces weight gain without inhibiting food intake in rodents. IL-15 suppresses lipogenesis, stimulates brown fat function, improves insulin sensitivity through weight loss and energy expenditure. In human, circulating IL-15 is negatively associated with body weight. In the immune system, IL-15 stimulates proliferation and differentiation of T cells, NK cells, monocytes and neutrophils. In the anti-obesity effects of IL-15, T cells and NK cells are not required, but leptin receptor is required. In summary, evidence from human and rodents supports that the pro-inflammatory cytokine IL-15 may enhance energy expenditure to protect the body from obesity and type 2 diabetes. The mechanism of IL-15 action remains to be fully uncovered in the regulation of energy expenditure.

    Tao Wang,Weiping Jia,Cheng Hu

    Obesity prevalence has increased in recent years. Lifestyle change fuels obesity, but genetic factors cause more than 50% of average variations in obesity. The advent of genome-wide association studies (GWAS) has hastened the progress of polygenic obesity research. As of this writing, more than 73 obesity susceptibility loci have been identified in ethnic groups through GWAS. The identified loci explain only 2% to 4% of obesity heritability, thereby indicating that a large proportion of loci remain undiscovered. Thus, the next step is to identify and confirm novel loci, which may exhibit smaller effects and lower allele frequencies than established loci. However, achieving these tasks has been difficult for researchers. GWAS help researchers discover the causal loci. Moreover, numerous biological studies have been performed on the polygenic effects on obesity, such as studies on fat mass- and obesity-associated gene (FTO), but the role of these polygenic effects in the mechanism of obesity remains unclear. Thus, obesity-causing variations should be identified, and insights into the biology of polygenic effects on obesity are needed.

    Shuwen Qian,Haiyan Huang,Qiqun Tang

    Adipose tissue is an important organ for energy homeostasis. White adipose tissue stores energy in the form of triglycerides, whereas brown adipocytes and recently identified beige adipocytes are specialized in dissipating energy by thermogenesis or contribution to dispose glucose and clear triglycerides in blood. The inverse correlation between the brown adipose tissue activity and body mass suggests its protective role against body fat accumulation. Thus, recruitment and activation of brown or beige adipose tissue become particularly appealing targets for increasing energy expenditure. Angiogenesis and sympathetic nerve signals are the fundamental determinants for brown and beige adipose tissue development, as well as for their metabolic functions. Secretary factors including BMPs can induce the development, the activation of brown or beige adipose tissue, which seem to be promising for therapeutic development.

    Juan Zheng,Shih-Lung Woo,Xiang Hu,Rachel Botchlett,Lulu Chen,Yuqing Huo,Chaodong Wu

    Metformin has been widely used as a first-line anti-diabetic medicine for the treatment of type 2 diabetes (T2D). As a drug that primarily targets the liver, metformin suppresses hepatic glucose production (HGP), serving as the main mechanism by which metformin improves hyperglycemia of T2D. Biochemically, metformin suppresses gluconeogenesis and stimulates glycolysis. Metformin also inhibits glycogenolysis, which is a pathway that critically contributes to elevated HGP. While generating beneficial effects on hyperglycemia, metformin also improves insulin resistance and corrects dyslipidemia in patients with T2D. These beneficial effects of metformin implicate a role for metformin in managing non-alcoholic fatty liver disease. As supported by the results from both human and animal studies, metformin improves hepatic steatosis and suppresses liver inflammation. Mechanistically, the beneficial effects of metformin on hepatic aspects are mediated through both adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent pathways. In addition, metformin is generally safe and may also benefit patients with other chronic liver diseases.

    Farhad Sahebjam,John M. Vierling

    Autoimmune hepatitis is a chronic liver disease putatively caused by loss of tolerance to hepatocyte-specific autoantigens. It is characterized by female predilection, elevated aminotransferase levels, autoantibodies, increased γ-globulin or IgG levels and biopsy evidence of interface hepatitis. It is currently divided into types 1 and 2, based on expression of autoantibodies. Autoantigenic epitopes have been identified only for the less frequent type 2. Although autoimmune hepatitis occurs in childhood, this review focuses on disease in adults. In the absence of pathognomonic biomarkers, diagnosis requires consideration of clinical, biochemical, serological and histological features, which have been codified into validated diagnostic scoring systems. Since many features also occur in other chronic liver diseases, these scoring systems aid evaluation of the differential diagnosis. New practice guidelines have redefined criteria for remission to include complete biochemical and histological normalization on immunosuppressive therapy. Immunosuppression is most often successful using prednisone or prednisolone and azathioprine; however, the combination of budesonide and azathioprine for non-cirrhotic patients offers distinct advantages. Patients failing standard immunosuppression are candidates for alternative immunosuppressive regimens, yet none of the options has been studied in a randomized, controlled trial. Overlap syndromes with either primary sclerosing cholangitis or primary biliary cirrhosis occur in a minority. Liver transplantation represents a life-saving option for patients presenting with acute liver failure, severely decompensated cirrhosis or hepatocellular carcinoma. Transplant recipients are at risk for recurrent autoimmune hepatitis in the allograft, and de novo disease may occur in patients transplanted for other indications. Patients transplanted for AIH are also at risk for recurrent or de novo inflammatory bowel disease. Progress in our understanding of the immunopathogenesis should lead to identification of specific diagnostic and prognostic biomarkers and new therapeutic strategies.

    Xijin Xu,Xiang Zeng,H. Marike Boezen,Xia Huo

    The adverse effects of electronic waste (e-waste) on the human body have stirred up concern in recent years. China is one of the countries that confront serious pollution and human exposure of e-waste, and the majority of the population is exposed to potentially hazardous substances that are derived from informal e-waste recycling processes. This study reviews recent reports on human exposure to e-waste in China, with particular focus on exposure routes (e.g., inhalation and ingestion) and several toxicities of human (e.g., endocrine system, respiratory system, reproductive system, developmental toxicity, neurotoxicity, and genetic toxicity). Pieces of evidence that associate e-waste exposure with human health effects in China are assessed. The role of toxic heavy metals (e.g., lead, cadmium, chromium, mercury, and nickel) and organic pollutants (e.g., polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyl (PCBs), polycyclic aromatic hydrocarbons (PAHs), polybrominated biphenyls (PBBs), polyhalogenated aromatic hydrocarbons (PHAHs), bisphenol A (BPA)) on human health is also briefly discussed.

    Nidhya Ganesan,Marie Moses Ambroise,Anita Ramdas,King Herald Kisku,Kulwant Singh,Renu G’ Boy Varghese

    Pulmonary alveolar microlithiasis is a rare disease characterized by intra-alveolar presence of microliths. This study reports an interesting case of pulmonary alveolar microlithiasis and provides a systematic review of cases reported from India. A 23-year-old female presented with a history of cough, wheeze, chest pain, and episodic wheeze for five months. Pulmonary function tests demonstrated an obstructive pattern, and chest X-ray showed fine micronodular opacities predominantly involving the middle and lower zones of both lungs. Transbronchial lung biopsy revealed the diagnosis. She responded well to inhaled steroid therapy. A systematic review of literature was performed and identified 73 cases of pulmonary alveolar microlithiasis reported from India. The mean (SD) age of the patients was 28.8 (14.9) years, with an almost equal male:female ratio. Many patients were asymptomatic at presentation. Breathlessness and cough were the most common symptoms, and the disease progressed into respiratory failure associated with cor pulmonale. About one-third of the cases were initially misdiagnosed and treated as pulmonary tuberculosis. Extra-pulmonary manifestations and co-morbidities were also evident in our series. This systematic review helps to determine epidemiological and clinical characteristics of pulmonary alveolar microlithiasis. Further research is needed to elucidate the etiopathogenesis, diagnosis, and therapeutic options, which are beneficial in developing and identifying cost-effective treatment for pulmonary alveolar microlithiasis.

    Jingmin Zheng,Jie Li,Xingxing Jiang,Bin Zhang

    Township hospitals, the main provider of rural primary healthcare in China, are severely understaffed. International studies on factors influencing rural working are increasing; however, studies on factors affecting the recruitment and retention of health workers in Chinese township hospitals are limited. The current study aims to understand the motivation of health workers and arrive at a systematic framework of pluralistic factors that would help support health workers in terms of receiving posts and remaining in posts in township hospitals. A three-stage integrated quantitative and qualitative methodology was employed. First, a survey on 120 directors of township hospitals was conducted to learn the latest status of health workers in township hospitals and distinguish existing problems. Second, after sending these problems back to the directors, an open-ended pen-and-paper survey was conducted to ask the directors to identify the factors influencing the attraction and retention of health workers in township hospitals. Third, four focus groups were conducted to gauge the underlying reasons. Five problems from the questionnaire survey were recognized, and numbers of thematic factors were identified at the individual, professional, and treatment environment from the pen-and-paper survey and focus group. Similar to other studies, this framing of both non-financial and financial elements affected the attraction and retention of health workers in township hospitals, thereby filling the gap in a Chinese context. Although several factors had been recognized earlier, our findings further highlighted the importance of these factors. Meanwhile, the factors identified in this study were barely explored in literature. This paper identifies and develops multi-faceted factors to call for a bundled package of multidimensional incentives if decision-makers get interested. The evidence-based findings in our study can be used to provide China-specific policy recommendations on how to recruit and retain health workers in rural areas of China.

    Luz Helena Alba,Nora Badoui,Fabián Gil

    Unhealthy behaviors of medical students influence their attitudes toward preventive counseling. The burden of chronic diseases is continually growing in developing countries, emphasizing the need for the increased role of general practitioners in preventive counseling. The objective of this study was to describe the effect of medical training on the risk profiles and attitudes of medical students toward preventive counseling in a Colombian university. Students in their first and fifth years of training were surveyed using the “Healthy Doctor= Healthy Patient” questionnaire to assess counseling attitudes; personal practices, such as risky drinking, smoking, inadequate nutrition, and non-compliance with physical activity recommendations; and the university environment. The association among these components was estimated, as well as the effect of the university environment. Risky drinking and smoking decreased from first to fifth year (59.3% vs. 37.1%, P = 0.021 and 31.5% vs. 25.9%, P = 0.51, respectively), whereas inadequate nutrition and non-compliance with physical activity recommendations increased. Physical activity (PA) was associated with positive counseling attitude (ORs: nutrition 7.6; alcohol 5.2; PA 10.6). Areas governed by institutional policies that are emphasized in the curriculum positively affected student practices. PA promoted preventive counseling and healthy lifestyles most effectively. Universities should therefore strengthen their preventive medicine curricula and modify social determinants.