Role of endogenous biological response modifiers in pathogenesis of infectious diseases

Biologic response modifiers (BRMs) interact with the host immune system and modify the immune response. BRMs can be therapeutically used to restore, augment, or dampen the host immune response. Although they have been used for decades, their clinical applications have been expanded in the past decade for diagnosis and treatment of many diseases including cancers, immunologic disorders, and infections. This article discusses endogenous biological response modifiers (ie, naturally occurring immunomodulators as a part of the host immune system), which play vital roles as regulators of both innate and adaptive immune responses.     

Overview of biologic response modifiers in infectious disease

The conventional treatment of infectious agents is increasingly encountering antimicrobial resistance. This resistance has led to an intense search for novel treatment modalities for infectious diseases. Elucidation of the mechanisms underlying the inhibitory activity of chemokines has been instrumental in the rational design of anti-human immunodeficiency virus chemokine drugs. The immune-based therapies, in combination with antimicrobial drugs, for viral hepatitis have attracted much attention. Recognition of toll-like receptors by synthetic immunomodulators is used for certain viral infections. New methodologies have the potential to identify novel targets and foster the development of individually tailored immunomodulatory drug treatments.     

Biologic response modifiers: relevance & repercussions

Biologic response modifiers (BRMs) are substances that occur naturally in the body. They can also be manufactured in the laboratory and then administered as targeted therapy. Undoubtedly BRMs will find expanded role in terminal illness like cancer where other therapies have failed. However, great caution must be exercised in prescribing these agents in chronic indolent diseases where potential for ultimate harm might outweigh short-term benefits.     

Vaccines and vaccine adjuvants as biological response modifiers

Vaccines have been used successfully for many years to prevent death and morbidity from infectious diseases. In the last two decades major advances in the fields of genetics and immunology have allowed a significant increase in the use of immunomodulatory drugs in a broad range of pathologic conditions. This article reviews several uses of immunomodulating properties of vaccines, both old and new, with a focus on cancer and autoimmune diseases. Special emphasis is placed on the historical aspects and current applications of the bacillus Calmette-Guérin vaccine, the first vaccine to be used in cancer immunotherapy.     

分枝杆菌快速检测方法及其应用

目的 本研究旨在探讨MGITTM荧光判读器快速检测分枝杆菌方法;探讨其应用价值.方法 对104例初治肺结核患者和30例健康对照痰标本进行常规涂片后,无论涂阴或涂阳,分别采用传统罗氏法(以下简称LJ),荧光判读器法(以下简称MMGIT)及MGITM960自动培养系统(以下简称AMGIT)进行培养与检测,并对结果进行比较和评价.结果 104例结核患者中,涂片阳性55例(阳性检出率52.88％),三种培养方法检测结果分别为MMGIT阳性65例(阳性检出率62.50％),AMGIT阳性67例(阳性检出率64.42％),LJ阳性62例(阳性检出率59.62％).30例健康对照涂片和培养均为阴性.MMGIT比LJ平均报阳时间早9.47天;其最短报阳时间比LJ快5天.与AMGIT相比,平均阳性时间晚1.56天.结论 荧光判读仪检测法是一个快速敏感的分枝杆菌检测方法;与MGITM960快速培养法功效一致,且经济实用,简单方便.值得基层结防机构临床应用.     

Biologicals and biological response modifiers: fourth modality of cancer treatment

Considerable progress has been made in the last 5 years toward the development of specific biological approaches to the treatment of cancer. The techniques of genetic engineering, mass cell culture, and improved techniques in protein and nucleic acid sequencing and synthesis have made available biologicals as specific, highly purified molecules that can be used in cancer therapy. While extensive clinical trials are needed to demonstrate that biologicals and biological response modifiers can provide a survival advantage for patients with cancer, the preliminary data indicate that these approaches can be useful in inducing responses in patients with clinically apparent disease. Further studies with these approaches in conjunction with surgery, radiotherapy, and chemotherapy should be helpful in definitively establishing biologicals and biological response modifiers as the fourth modality of cancer treatment.     

Interferon and interleukin-2 induced spontaneous cell-mediated cytotoxicity: a preliminary evaluation

Summary The contribution of natural cell-mediated cytotoxicity and its modulation with biological response modifiers in antitumour immunity was evaluated in patients with precancers and cancers of the oral cavity. The results were compared to those in normal controls. Both groups of patients showed highly significant depression of the natural killer cell activity. This depression was stage-related, suggesting an influence of tumour or tumour products on this activity. Depression in augmentation of this cytotoxicity was evident in both patient groups with cancers and precancers, suggesting a defect in the response of killer cells to biological response modifiers for reasons other than the tumour per se.     

Unravelling modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: update on genetic modifiers

Pathogenic mutations in the tumour suppressor genes BRCA1 and BRCA2 confer increased risks for breast and ovarian cancer and account for approximately 15% of the excess familial risk of breast cancer amongst first-degree relatives of patients with breast cancer. There is considerable evidence indicating that these risks vary by other genetic and environmental factors clustering in families. In the past few years, based on the availability of genome-wide association data and samples from large collaborative studies, several common alleles have been found to modify breast or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. These common alleles explain a small proportion of the genetic variability in breast or ovarian cancer risk for mutation carriers, suggesting more modifiers remain to be identified. We review the so far identified genetic modifiers of breast and ovarian cancer risk and consider the implications for risk prediction. BRCA1 and BRCA2 mutation carriers could be some of the first to benefit from clinical applications of common variants identified through genome-wide association studies. However, to be able to provide more individualized risk estimates, it will be important to understand how the associations vary with different tumour characteristics and their interactions with other genetic and environmental modifiers.     

结核分枝杆菌katG基因突变对异烟肼耐药性的影响

目的探讨结核分枝杆菌katG基因突变TGG328TTT(Trp328Phe)对异烟肼耐药性的影响。方法以结核分枝杆菌标准株H37Rv和临床突变株DNA为模板,采用PCR扩增野生型和双突变型(含Trp328Phe与Met420Thr)katG基因,采用重叠延伸PCR技术构建单突变型(Trp328Phe)katG基因。将各katG基因重组至质粒pET22b(+),再导入表达宿主菌BL21(DE3)pLySs中,IPTG诱导目的蛋白表达,亲和层析法对重组KatG蛋白进行分离纯化。通过各重组KatG蛋白与过氧化氢和邻联大茴香胺反应,检测受试菌过氧化氢酶和过氧化物酶的活性。结果成功获得纯化的KatG蛋白。相比野生型KatG(19.05U/mg和7.05×10-3 U/mg),单突变型KatG(10.50U/mg和2.23×10-3 U/mg)过氧化氢酶和过氧化物酶活性分别下降44.9%和68.3%,双突变型KatG(11.88U/mg和3.31×10-3 U/mg)则分别下降37.6%和53.0%。结论 katG基因(Trp328Phe)突变引起KatG酶活性部分缺失,与异烟肼耐药有关,可作为耐药菌株基因检测的标志用于基因芯片的开发。双突变时KatG蛋白活性较高,提示katG-328TTT具有代偿性突变的作用。     

蚤与鼠疫菌之间的生物学关系

鼠疫是一种自然疫源性疾病。在它的3个要素中，人们往往更偏重于研究鼠疫菌和宿主之间的关系，而忽视了传播媒介的重要作用。然而，实际上蚤在动物鼠疫的流行和保存过程中起着非常重要的作用。作通过献积累，列举了蚤与鼠疫菌之间的4种生物学关系而得出结论：蚤与鼠疫菌之间的生物学关系绝非一般的生物学概念上的寄生关系。在动物鼠疫流行过程中，这种关系的动态平衡是起决定性作用的。     

安徽省420株结核分枝杆菌对一线和二线抗结核药物药敏结果分析

目的研究并分析安徽地区420例结核分枝杆菌对一线、二线抗结核药物菌耐药情况,为结核病临床治疗和结核病控制提供科学依据。方法采用绝对浓度法对420例结核分枝杆菌临床分离株进行一线、二线抗结核药物敏感试验。结果对一线抗结核药物总耐药率和耐多药率分别是29．05％和14．52％;其中初治耐药率和耐多药率分别是15．93％、6．79％,复治耐药率和耐多药率分别是52．86％、30．0％;RIF、INH、SM、EMB耐药率分别是22．14％、20．0％、17．38％和0．95％。抗二线结核药物总耐药率为22．62％,其中左氧氟沙星和丙硫乙烟胺的耐药率较高,分别为13．33％（56／420）和12．86％（54／420）,年龄段41～60岁耐药率均显著高于其他年龄段（P〈0．05）;男性和女性病例组间均无统计学显著性差异（P〉0．05）。结论安徽地区结核菌耐药情况仍然十分严重,应加强抗结核药物的耐药性监测,同时根据药敏试验结果选择科学有效的化疗方案。     

Progress in the therapy of myelodysplastic syndromes

Summary The progress in the therapy of the myelodysplastic syndromes has been far from spectacular during recent years. No currently available treatment has been shown to be consistently effective in producing sustained improvement in hematopoiesis or in delaying leukemic evolution. With regard to both quantity and quality of life, no other treatment has been proven superior to classical supportive treatment, with the possible exception of bone marrow transplantation in younger patients. While in selected cases anecdotal successes have been noted with the use of hormonal therapy, some differentiation inducers, e.g. vitamin A- en D-analogues, have not hold their promises in placebo controlled trials. Attempts to induce complete remissions in MDS with antileukemic treatment have usually been unsuccessful. Toxicity is substantial and a considerable proportion of patients fare worse with chemotherapy than with standard supportive care. Recently, a flood of reports has appeared on the use of biological response modifiers e.g. cytokines and growth factors in the treatment of MDS. Perhaps some of these hold promises for a new era in MDS, but the data are preliminary and no follow-up on long term survival is at hand.     

Refeeding and metabolic syndromes: two sides of the same coin

Refeeding syndrome describes the metabolic and clinical changes attributed to aggressive rehabilitation of malnourished subjects. The metabolic changes of refeeding are related to hypophosphatemia, hypokalemia, hypomagnesemia, sodium retention and hyperglycemia, and these are believed to be mainly the result of increased insulin secretion following high carbohydrate intake. In the past few decades, increased consumption of processed food (refined cereals, oils, sugar and sweeteners, and so on) lowered the intake of several macrominerals (mainly phosphorus, potassium and magnesium). This seems to have compromised the postprandial status of these macrominerals, in a manner that mimics low grade refeeding syndrome status. At the pathophysiological level, this condition favored the development of the different components of the metabolic syndrome. Thus, it is reasonable to postulate that metabolic syndrome is the result of long term exposure to a mild refeeding syndrome.Refeeding syndrome represents a group of metabolic and clinical changes that occur in severely malnourished patients undergoing aggressive nutritional support.¹ Metabolic changes include: hypophosphatemia, hypokalemia, hypomagnesemia, sodium retention and hyperglycemia.² Although clinical changes cover most organ systems, including cardiovascular, gastrointestinal, musculoskeletal, respiratory, neurological and hematological abnormalities, these changes are the outcome of the metabolic changes in a scale that is synergistically related to the degree of the metabolic changes, in which under severe conditions multiple organ failure may occur leading to death.¹ On the other hand, metabolic syndrome is a name for a group of risk factors that occur together, increasing the risk for coronary artery disease, stroke and type 2 diabetes. These factors are: central obesity, high triglycerides, low high-density lipoprotein cholesterol, elevated blood pressure and raised blood glucose.³ Classification according to the US National Cholesterol Education Program Adult Treatment Panel III requires the presence of at least three of the above factors.³The pathophysiology of refeeding syndrome is related to the fact that under conditions of starvation, the body shifts from carbohydrate to fat and protein utilization (state of catabolism) to produce glucose and energy.² Therefore malnutrition, which usually exists in different disease states including cancer, Marasmus/Kwashiorkor, neurological problems, respiratory diseases, gastrointestinal and liver diseases, and so on,^{2, 4} is the major risk factor for refeeding syndrome.^{2, 4} Upon refeeding, especially with carbohydrate, the body shifts back instantaneously to carbohydrate metabolism (state of anabolism).² Concomitantly, insulin secretion is increased leading to an increase in the cellular uptake of glucose and macrominerals (in particular phosphorus, potassium and magnesium) mainly occurring in the liver and muscles, and thus resulting in hypophosphatemia, hypomagnesaemia and hypokalemia.² Simultaneously, insulin resistance prevails as indicated by the coexistence of hyperglycemiam and hyperinsulinemia,^{1, 2, 4} which reduces sodium clearance leading to sodium retention and thus resulting in fluid retention and expansion of the extracellular fluid volume.^{1, 2} Thus, the clinical manifestations of these macromineral abnormalities have serious deleterious effects, some of which are hypotension, bradycardia, weakness, heart failure and arrhythmias.⁴ In brief, refeeding syndrome is the consequence of the ingestion of a high carbodydrate–low macrominerals diet following prolonged fasting.In normal subjects and under normal conditions, energy metabolism is known to fluctuate diurnally, as meal ingestion causes a shift to carbohydrate metabolism and an increase in both energy expenditure and carbohydrate oxidation.⁵ Meal ingestion ensues an increase in cellular uptake and utilization of glucose and macrominerals (predominantly phosphorus, potassium and magnesium), as a result of increased insulin secretion and demand for metabolic processes (for example, phosphorylation and so on). Therefore, plasma status of these macrominerals depends on insulin secretion (that is highly dependent on carbohydrate intake) and their meal content of marominerals. Ingestion of pure glucose is known to be associated with a reduction in plasma concentration of these macrominerals and their inclusion in a meal was reported to improve their status.⁶ Thus, it is reasonable to postulate that under normal conditions the postprandial metabolic changes following the ingestion of high carbohydrate–low macrominerals diet resemble those of the refeeding syndrome but to a lower extent. Hence, what remains to be elucidated is whether the dietary changes that have occurred in the past few decades favored the consumption of high carbohydrate–low macrominerals diets and thus have exacerbated these metabolic changes.Evidence from epidemiological studies reveal that the increased prevalence of the ‘Western diet'' is implicated in the increased prevalence of obesity, diabetes and hypertension, observed in Africa, Asia, South America, Australia/New Zealand and Oceania.^{7, 8, 9, 10} Western diet is characterized by the consumption of refined (cereals) carbohydrates, sugars, sweeteners (especially high fructose corn syrup), oils and fats.^{7, 8} The implication of the Western diet has further been proposed to promote the incidence of insulin resistance¹¹ and metabolic syndrome.¹² Furthermore, the increased intake of fructose-based sweeteners has been also reported to be associated with the development of metabolic syndrome and obesity.¹³ This association was proposed to be related to its capacity to “sequester phosphate”,¹⁴ stimulate triglyceride synthesis^{13, 15, 16} and promote insulin resistance.^{13, 17}During the past few decades, the major changes in dietary habits, as have been discussed earlier in this paper, are mainly related to a dramatic increase in the intake of: (1) macromineral (P, K and Mg)-free commodities, such as oils, sugar and sweeteners, which contains negligible amounts of the above macrominerals) and (2) refined cereals commodities, where refinement is known to reduce the content of these macrominerals by about 70%. Cereals are known to contribute to more than 50% of the total energy intake in most countries;¹⁸ therefore, the shift from whole grain cereals (whole wheat, brown rice) to refined cereals would be expected to result in substantial reduction in the intake of these macrominerals. A further reduction would be expected from the increased consumption of macrominerals-free commodities. In developed and transitional countries, the consumption of these (above) commodities is known to be inversely related to socioeconomic status, mainly because of their high energy density (kcal g⁻¹ food) and low energy cost (US$ per 1000 kcal). This has also been proposed to be an important factor behind the high prevalence of obesity and metabolic syndrome among urban people of low socioeconomic status.¹⁹It is well known that in the past few decades, urbanization has increased in most countries. The changes in the consumption of the different food groups based on the change in gross national product per capita of the country and change in urbanization was studied by Popkin and Gordon–Larsen⁹ and Drewnowski and Popkin.²⁰ Increased urbanization worldwide was found to be associated with increased consumption of vegetable fats and sugars. At the same time, a direct relationship was reported to be present between urbanization and gross national product per capita and the increase in the consumption of fats and sweeteners. High gross national product per capita was associated with higher consumption of vegetable, animal fats and sugars with a sharp decrease in the consumption of complex carbohydrates.²⁰ Rapid urbanization worldwide has a major influence on accelerating the nutrition transition. It was also reported that an increased production and consumption of sweeteners derived from starch has been observed in the last several decades.²¹ For example, in the year 2000, the caloric consumption of sweeteners increased by one-third more than in the year 1962. Similarly, in the United States, the daily caloric intake was reported to increase, mainly from energy-dense and nutritiously poor food choices,^{8, 22, 23, 24, 25, 26, 27} such as fast food, salty snacks^{8, 22, 23, 24} and added caloric sweeteners.^{8, 21, 28} In addition to fast food choices lacking essential nutrients,^{8, 29, 30} fruit and vegetable consumption was observed to be far lower than the recommended levels.^{8, 21, 22}It can therefore be deduced that the high intake of refined carbohydrates, fats and sweeteners accompanied with the low intake of fruits and vegetables, leads to a diet that is deficient or suboptimal in vitamins and minerals (including potassium, phosphorus and magnesium). Thus, the increased prevalence of metabolic syndrome among people consuming high quantities of commodities containing low levels of these macrominerals may implicate these macrominerals in the development of metabolic syndrome, as is the case in its implication in refeeding syndrome. Thus, decreased intake of these macrominerals would be expected to undermine their postprandial concentration, and it is yet to be determined whether such undermining would have any health implications. Such a question can be clarified by looking at the relationship between these macrominerals and the different components of the metabolic syndrome.     

Management of rheumatoid arthritis: the 2012 perspective

Management of rheumatoid arthritis (RA) has improved over the last 10 years. These changes have been monitored in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) observational cohort, and clinical remission has become a realistic goal. However, we should recognize that the ultimate goal of treatment is to improve long-term outcomes. These improvements have been achieved not only by new drugs, but also by the overall approach toward treating patients. Biologics in RA have been successful; however, safety concerns and pharmacoeconomical issues are still debated. Protein kinase inhibitors have been developed, and can be called “molecular-targeting antirheumatic drugs” (MTARDs), as opposed to “disease-modifying antirheumatic drugs.” In comparison with biologics, oral MTARDs should be less expensive; however, their safety profile should be confirmed. Considering the limitations of randomized trials, it is encouraged to conduct studies based on daily practice. It is time to consider the application of the evidence generated from “our” patients to patients in daily practice, namely institute-based medicine as opposed to evidence-based medicine, of which “IORRA-based medicine” would be representative. Finally, there remains much for us rheumatologists to do for our patients, including patient-perspective approaches.     

Hepatitis B reactivation after chemotherapy: two decades of clinical research

Hepatitis due to hepatitis B virus reactivation after cytotoxic or immunosuppressive therapy is a serious cause of liver-related morbidity and mortality. With the characterization of the underlying pathogenesis, much progress in the management of this important clinical problem has been made in the past 2 decades. By year 2008, it is mandatory to screen for hepatitis B surface antigen status before initiating intensive chemotherapy or immunosuppressive therapy. All those who are hepatitis B surface antigen positive should be started on preemptive nucleos(t)ide analogues. However, there remains important issues, such as the type and duration of nucleos(t)ide analogue therapy, which need to be understood. As not all hepatitis B surface antigen-positive patients will suffer from HBV reactivation, it is therefore useful to identify risk factors related to HBV reactivation so that patients will not be treated unnecessarily with nucleos(t)ide analogues. To date, a high baseline level of viral replication, as reflected by high serum HBV DNA level, positive serum hepatitis B e antigen, and a high intrahepatic covalently closed circular DNA level, is the most important predictor for HBV reactivation. Recently, there has been an increased awareness of reactivation of occult hepatitis B virus, especially in hepatitis B virus endemic area, such as the Asia-Pacific region. Careful epidemiological study will be needed to clarify the impact of occult hepatitis B infection in patients treated with cytotoxic or immunosuppressive therapy.