Animals,disease, and man: making connections

The intricate causal relationships between disease in man and disease in animals first began to be elucidated in the mid-19th century. Although the connections between animal and human disease are now generally understood, individuals as well as societies remain slow to act on this knowledge. This paper examines the gradual recognition of these disease connections and explores the parallel theme of man's reluctance to appreciate the implications of these connections. It identifies factors that have inhibited the realization of the links between disease in man and animals, and discusses several milestones in the scientific elucidation of these links. Beginning with emerging concerns over the relationship between bovine and human tuberculosis in the 1860s, it follows the discovery of insect vectors, animal reservoirs, and the links between animals, influenza, and man. Despite warnings of the potential significance for human disease of patterns of changes in the relationship with animals and the natural world, scientists have continued to treat human and animal health as largely independent disciplines, while historians too have neglected this important aspect of human disease.     

The complication of coinfection

Infectious disease remains one of the largest burdens on humankind. Even with modern medical and public health standards, infectious disease remained the No. 1 killer worldwide at the turn of the century. Often, the most costly disease burdens come from multiple infections at once, i.e., coinfection. Influenza, an annual infection often considered relatively harmless, can increase susceptibility to both deadly bacterial pneumonia and childhood ear infections. Major health threat HIV rarely kills a patient on its own, but instead allows for opportunistic infections and re-emergence of infections such as tuberculosis. What generates these unique relationships is not well understood; herein, we examine in detail three types of coinfection and the unique interactions between infectious agents as well as with the host in each setting. We also begin to address how we may aid further understanding of coinfection and what questions need to be addressed to help direct future treatments.     

结核分枝杆菌耐氟喹诺酮类药物的分子机制研究进展

结核病是由结核分枝杆菌(Mycobacterium tuberculosis)通过空气传播引起人类感染的慢性传染病,耐药结核分枝杆菌的流行是目前结核病防治的世界难题。氟喹诺酮类药物是人工合成药物,应用于耐药结核的临床治疗中,在治疗中起着核心的作用。但近年来,氟喹诺酮类药物的抗性菌株不断出现,愈发增加了结核病治疗的困难与治疗失败风险。在临床中氟喹诺酮药物的靶点比较清楚,是结核分枝杆菌的DNA旋转酶。目前发现结核分枝杆菌耐氟喹诺酮类药物的机制主要包括药物靶点DNA旋转酶的关键氨基酸改变、药物外排泵系统、细菌细胞壁厚度的增加以及喹诺酮抗性蛋白MfpA介导的DNA旋转酶活性调控。其中在氟喹诺酮靶标DNA旋转酶功能活性改变的耐药机制方面,编码DNA旋转酶基因突变一直是研究的热点,但近年来发现DNA旋转酶的调控蛋白MfpA以及DNA旋转酶的修饰在细菌耐药性中起着重要的作用,相关机制还亟待发现。本文综述了当前结核分枝杆菌耐氟喹诺酮类药物的作用机制,旨在为研发精准诊断技术和药物发掘提供科学理论基础和参考。     

The doctrine of specific etiology

Modern medicine is often said to have originated with nineteenth century germ theory, which attributed diseases to bacterial contagions. The success of this theory is often associated with an underlying principle referred to as the “doctrine of specific etiology”. This doctrine refers to specificity at the level of disease causation or etiology. While the importance of this doctrine is frequently emphasized in the philosophical, historical, and medical literature, these sources lack a clear account of the types of specificity that it involves and why exactly they matter. This paper argues that nineteenth century germ theory involves two types of specificity at the level of etiology. One type receives significant attention in the literature, but its influence on modern medicine has been misunderstood. A second type is present in this model, but it has been completely overlooked in the extant literature. My analysis clarifies how these types of specificity led to a novel conception of etiology that continues to figure in medicine today.     

Evaluating bacterial pathogen DNA preservation in museum osteological collections

Reports of bacterial pathogen DNA sequences obtained from archaeological bone specimens raise the possibility of greatly improving our understanding of the history of infectious diseases. However, the survival of pathogen DNA over long time periods is poorly characterized, and scepticism remains about the reliability of these data. In order to explore the survival of bacterial pathogen DNA in bone specimens, we analysed samples from 59 eighteenth and twentieth century individuals known to have been infected with either Mycobacterium tuberculosis or Treponema pallidum. No reproducible evidence of surviving pathogen DNA was obtained, despite the use of extraction and PCR-amplification methods determined to be highly sensitive. These data suggest that previous studies need to be interpreted with caution, and we propose that a much greater emphasis is placed on understanding how pathogen DNA survives in archaeological material, and how its presence can be properly verified and used.     

Lionel Penrose and the concept of normal variation in human intelligence

Lionel Penrose (1898-1972) was an important leader during the mid-20th century decline of eugenics and the development of modern medical genetics. However, historians have paid little attention to his radical theoretical challenges to mainline eugenic concepts of mental disease. Working from a classification system developed with his colleague, E. O. Lewis, Penrose developed a statistically sophisticated and clinically grounded refutation of the popular position that low intelligence is inherently a disease state. In the early 1930s, Penrose advocated dividing "mental defect" (low intelligence) into two categories: "pathological mental defect," which is a disease state that can be traced to a distinct genetic or environmental cause, and "subcultural mental defect," which is not an inherent disease state, but rather a statistically necessary manifestation of human variation in intelligence. I explore the historical context and theoretical import of this contribution, discussing its rejection of typological thinking and noting that it preceded Theodosius Dobzhansky's better-known defense of human diversity. I illustrate the importance of Penrose's contribution with a discussion of an analogous situation in contemporary medicine, the controversial practice of using human growth hormone injections to treat "idiopathic short stature" (mere diminutive height, with no distinct cause). I show how Penrose's contributions to understanding human variation make such treatments appear quite misguided.     

Microarrays for public health: genomic epidemiology of tuberculosis

In response to a large local school-based outbreak of tuberculosis, we have been evaluating the utility of microarray bacterial genomic analysis in outbreak management. After initial comparison of the isolate from the index case with Mycobacterium tuberculosis H37Rv, it was possible to design robust PCRs directed towards strain-specific deletions. Rapid PCR analysis of isolates proved valuable in determining whether or not other isolates were compatible with the outbreak strain and further microarray studies revealed genetic markers that could be used to discriminate between locally circulating strains.We suggest that this approach forms the basis for developing rapid local genotyping schemes applicable to M. tuberculosis and that application to other pathogens warrants consideration.     

Joint Effects of Smoking and Silicosis on Diseases to the Lungs

Smokers are subject to being more susceptible to the long-term effects of silica dust, whilst it remains unclear whether the joint effect of smoking and silicosis differs amongst diseases to the lungs; this study aims to address this knowledge gap. This was a historical cohort study comprised of 3202 silicotics in Hong Kong during 1981–2005 who were followed up till 31/12/2006. We estimated the standardized mortality ratio (SMR) in the smoking and never smoking silicotics using the mortality rates of male general population indiscriminately by smoking status, but these SMRs were regarded as biased. We adjusted these biased SMRs using “smoking adjustment factors (SAF)”. We assessed the multiplicative interaction between smoking and silicosis using ‘relative silicosis effect (RSE)’ that was the ratio of SAF-corrected SMR of smoking silicotics to the never smokers. A RSE differs significantly from one implies the presence of multiplicative interaction. A significant excess SMR was observed for respiratory diseases (lung cancer, chronic obstructive pulmonary diseases [COPD], silicosis) and other diseases to the lungs (pulmonary heart disease, tuberculosis). All the ‘biased-SMRs’ in smokers were higher than those in never smokers, but the SAF-corrected SMRs became higher in never smokers. The RSE was 0.95 (95%CI: 0.37–3.55), 0.94 (95%CI: 0.42–2.60), and 0.81 (95%CI: 0.60–1.19) for lung cancer, COPD, and silicosis; whilst it was 1.21 (95%CI: 0.32–10.26) for tuberculosis and 1.02 (95%CI: 0.16–42.90) for pulmonary heart disease. This study firstly demonstrated the joint effect of smoking and silicosis may differ amongst diseases to the lungs, but power is limited.     

三种免疫学方法在矽肺合并肺结核诊断中的价值研究

目的:探讨T淋巴细胞酶联斑点实验(T-SPOT)、结核菌素皮肤试验(tuberculin test,TST)以及结核抗体(tuberculosis antibody)在矽肺合并肺结核(pulmonary silicosis complicated with tuberculosis)诊断中的应用价值。方法:收集2015年8月7日至2016年5月20日确诊为矽肺结核感染患者41例、非矽肺结核患者90例、健康体检学生对照组40例,对三组人群经以上免疫学方法检测的结果进行统计分析。结果:1)矽肺结核、非矽肺结核及健康人群中T-SPOT阳性率分别为73.17%、93.33%、15%,三者两两比较差异有统计学意义;矽肺结核、非矽肺结核及健康人群中TST阳性率分别为58.54%、88.89%、32.5%,非矽肺结核患者与健康人群及矽肺结核患者之间,差异均有统计学意义,但矽肺结核患者与健康人群之间,差异无统计学意义;矽肺结核、非矽肺结核及健康人群中结核抗体阳性率分别为36.58%、42.22%、52.5%,三者两两比较差异均无统计学意义。2)三种检测方法在矽肺结核患者中的敏感性分别为73.17%、58.54%、36.58%,差异有统计学意义,其中T-SPOT及TST的敏感性均高于结核抗体方法(P0.05);特异性分别为85%、67.5%、47.5%,其中T-SPOT的特异性高于结核抗体方法(P0.05);阳性预测值分别为83.33%、64.86%、41.67%,阴性预测值分别为75.56%、61.36%、42.22%,三种方法的阳性及阴性预测值存在差异,均有统计学意义。3)T-SPOT在I、II、III期矽肺结核检测的阳性率分别为52.38%、94.12%、100%,I期与II期或III期的阳性率之间差异有统计学意义,II期与III期之间阳性率差异无统计学意义。结论:T-SPOT方法具有较高的敏感性及特异性,对矽肺结核辅助诊断及临床分期具有较好的应用价值。     

Robert Koch and the white death: from tuberculosis to tuberculin

The German medical bacteriologist Robert Koch is commonly considered one of the founding fathers of medical bacteriology. His investigations into the aetiology of tuberculosis uncovered the pathogen of this condition, the tubercle bacillus today known as Mycobacterium tuberculosis, in 1882. This work can be seen as a cornerstone of contemporary medical bacteriology, its technologies and methods. It has often been asked how such successful research connected to the tuberculin episode of 1890/91, when Koch produced a medicine for that disease, which spectacularly failed when applied in practice. The analysis concentrates on the path of mostly experimental investigations which Koch followed between 1882 and 1890. From Koch's laboratory notes it becomes clear that tuberculin therapy did in fact work in Koch's laboratory, even though it failed to do so almost anywhere else. The clue to this contradictory picture lies in the peculiar nature of Koch's understanding of tuberculosis as a disease e.g. his reliance an animal experiments, which essentially differed from what many of his contemporaries held as essentials of that condition.     

Cloning of the gene encoding a protective Mycobacterium tuberculosis secreted protein detected in vivo during the initial phases of the infectious process

The existence of therapeutic agents and the bacille Calmette-Guérin (BCG) vaccine have not significantly affected the current tuberculosis pandemic. BCG vaccine protects against serious pediatric forms of tuberculosis but not against adult pulmonary tuberculosis, the most common and contagious form of the disease. Several vaccine candidates, including Mycobacterium tuberculosis recombinant proteins formulated in newer adjuvants or delivered in bacterial plasmid DNA have recently been described. An attractive source of vaccine candidates has been M. tuberculosis Ags present in culture supernatants of the initial phases of the bacterial growth in vitro. In this study we describe an Ag discovery approach to select for such Ags produced in vivo during the initial phases of the infection. We combined RP-HPLC and mass spectrometry to identify secreted or shed M. tuberculosis proteins eliminated in animal urine within 14 days after the infection. A peptide containing sequence homology with a hypothetical M. tuberculosis protein was identified and the recombinant protein produced in Escherichia coli. The protein was recognized by Ab (IgG2a and IgG1) and T cells (Th1) of mice infected with M. tuberculosis and by lymphoid cells from healthy donors who had a positive purified protein derivative skin test but not from tuberculosis patients. Moreover, this Ag induced protection in mice against M. tuberculosis at levels comparable to protection induced by BCG vaccine. These results validate the Ag discovery approach of M. tuberculosis proteins secreted or shed in vivo during the early phases of the infection and open new possibilities for the development of potential vaccine candidates or of markers of active mycobacterial multiplication and therefore active disease.     

Ancient Deforestation Revisited

The image of the classical Mediterranean environment of the Greeks and Romans had a formative influence on the art, literature, and historical perception of modern Europe and America. How closely does is this image congruent with the ancient environment as it in reality existed? In particular, how forested was the ancient Mediterranean world, was there deforestation, and if so, what were its effects? The consensus of historians, geographers, and other scholars from the mid-nineteenth century through the first three quarters of the twentieth century was that human activities had depleted the forests to a major extent and caused severe erosion. My research confirmed this general picture. Since then, revisionist historians have questioned these conclusions, maintaining instead that little environmental damage was done to forests and soils in ancient Greco-Roman times. In a reconsideration of the question, this paper looks at recent scientific work providing proxy evidence for the condition of forests at various times in ancient history. I look at three scientific methodologies, namely anthracology, palynology, and computer modeling. Each of these avenues of research offers support for the concept of forest change, both in abundance and species composition, and episodes of deforestation and erosion, and confirms my earlier work.     

Wanted,an Anthrax vaccine: Dead or Alive?

It has been more than 100 years since the realization that microbes are capable of causing disease. In that time, we have learned a great deal as to how each organism has adapted to the immune system so as to avoid elimination. As well, we have also learned an immense amount since Louis Pasteur first proposed that the solution to infectious diseases was to culture the microbes and attenuate their virulence, so as to use them as vaccines. From the optimism and promise of the 19th century and immunization as the ultimate answer to the invasion by the microbial world, to the scientific realities of the 21st century, it is of interest to retrace the steps of the earliest microbiologists cum immunologists, to realize how far we've come, as well as how far we yet have to go. This editorial focuses on the history of anthrax as a microbial disease, and the earliest efforts at producing a vaccine for its prevention.     

The rise and fall of bacterial clones: Streptococcus pneumoniae

Globally spreading bacterial strains belong to clonal types that have the capacity to colonize, spread and cause disease in the community. Recent comparative genomic analyses of well-defined clinical isolates have led to the identification of bacterial properties that are required for the successful spread of bacterial clones. In this Review, we discuss the evolution of bacterial clones, the importance of recombination versus mutations for evolution of clones, common methods used to study clonal relationships among bacteria, factors that may contribute to the clonal spread of bacteria and the potential relevance of bacterial clones to clinical disease. We focus on the common pathogen Streptococcus pneumoniae, although other bacteria are also briefly discussed, such as Helicobacter pylori, Staphylococcus aureus and Mycobacterium tuberculosis.     

The granuloma in cryptococcal disease

Although we have recognized cryptococcosis as a disease entity for well over 100 years, there are many details about its pathogenesis which remain unknown. A major barrier to better understanding is the very broad range of clinical and pathological forms cryptococcal infections can take. One such form has been historically called the cryptococcal granuloma, or the cryptococcoma. These words have been used to describe essentially any mass lesion associated with infection, due to their presumed similarity to the quintessential granuloma, the tubercle in tuberculosis. Although clear distinctions between tuberculosis and cryptococcal disease have been discovered, cellular and molecular studies still confirm some important parallels between these 2 diseases and what we now call granulomatous inflammation. In this review, we shall sketch out some of the history behind the term “granuloma” as it pertains to cryptococcal disease, explore our current understanding of the biology of granuloma formation, and try to place that understanding in the context of the myriad pathological presentations of this infection. Finally, we shall summarize the role of the granuloma in cryptococcal latency and present opportunities for future investigations.     

New genetic approaches shed light on TB virulence

Although tuberculosis has been studied for more than a century, insights into the molecular mechanisms by which it causes disease remain fairly limited. The current genetic boom in this system promises to reveal new virulence mechanisms, making this an exciting time to be studying this disease. Long considered a technical "poor relation", tuberculosis research has developed into a source for creative techniques and ideas. In the midst of this development, it is important to keep in mind the limitations of each new approach that is employed to study this organism. This review examines the genetic approaches that are currently being used to study tuberculosis, with an emphasis on new developments that promise to improve our understanding of the pathogenic mechanisms of Mycobacterium tuberculosis.     

Rib lesions in chronic pulmonary tuberculosis

The diagnosis of skeletal tuberculosis in human remains has traditionally been based upon the detection of secondary skeletal lesions which result from hemotogenous dissemination of tubercle bacilli (e.g., Pott's disease). Since such lesions develop in less than 7% of cases of human tuberculosis, the paleodemography and paleoepidemiology of this disease have been difficult to assess from skeletal remains. This study presents a new diagnostic approach to tuberculosis, focusing on the skeletal manifestations of chronic pulmonary disease (which comprises approximately 90% of human-form tuberculosis). Four hundred forty-five skeletal remains from persons dying of tuberculosis during the first half of the 20th century were examined. A total of 70/445 (16%) exhibited skeletal lesions in one or more locations as a response to infection. Of these 70, 39 (56%) were found to display a specific set of lesions restricted to the internal aspect of the ribs. These lesions take one of two forms: (1) diffuse periostitis or (2) localized abscess, and appear to correspond to areas of chronic pulmonary infection. The diffuse type of rib lesion is more commonly observed than the localized type. In our observations (and according to the natural history of tuberculosis) the occurrence of chronic pulmonary tuberculosis is usually mutually exclusive with hematogenous dissemination to secondary bone locations. Thus, the detection of rib lesions in cases of chronic pulmonary disease increases the absolute sample size of skeletal tuberculosis by a factor of two in this study.     

Surgery and national identity in late nineteenth-century Vienna

For historians of medicine, the professor Theodor Billroth of the University of Vienna was the leading European surgeon of the late nineteenth century and the personification of intervention by organ or body part removal. For social and political historians, he was a German nationalist whose book on medical education heralded the rise of anti-Semitism in the Austrian public sphere. This article brings together and critically reassesses these two hitherto separate accounts to show how, in a period of dramatic social and political change, Viennese surgery split into two camps. One, headed by Billroth, was characterized by an alliance with the German educational model, German nationalism leading to racial anti-Semitism and an experimental approach to the construction of surgical procedure, which heavily relied on the methods of pathological physiology. The other, which followed a long Austrian tradition, stood for a clinically oriented and strictly organized medical education that catered to an ethnically and socially diverse population and, simultaneously, for an anatomically oriented surgery, largely of the locomotor apparatus. This study shows how, in a major centre of medical education and capital of a multiethnic empire, surgical and national identities were forged together.