Bodies and borders: a new cultural history of medicine

Both medicine and the history of medicine have seen many changes in the last four decades. The way we tell the story of medical developments no longer concentrates on the important doctors and their ideas. The influences of social history in the 1960s and 1970s and cultural history in the 1980s and 1990s have broadened and enriched the interpretations of our medical past. The social historians have helped us to include politics, economics, and the leading ideas of any period we wanted to study; the cultural approach has added ethnography as well as an emphasis on language or discourse.Today there is a new history of medicine, one far more willing to cross disciplinary boundaries to ask questions about how we know what we know and why we do what we do.This article highlights some of the work in the adjoining fields of medical anthropology and of literature and medicine to demonstrate new interests, new questions, and new methods of inquiry. However, although we have cast our nets far more widely in the process of professionalizing the history of medicine, there is a question about whether we have lost the appeal to one of our core constituencies: medical students and physicians. We need to welcome some of the new changes in medical history as in medicine itself; the common goal is to achieve a better understanding of what we have done and what we are doing.     

Structural characterization of LNA and alpha-L-LNA hybridized to RNA

LNA and alpha-L-LNA are promising candidates for the development of efficient oligonucleotide-based therapeutic agents. Here, we present a short overview of the structural results we have obtained for LNA:RNA and alpha-L-LNA:RNA hybrids. Specifically, we have shown that LNA acts as an A-type mimic, while alpha-L-LNA acts as a B-type mimic when built into oligonucleotides.     

The flow cytometric analysis of cytokines using multi-analyte fluorescence microarray technology

Cytokines, which are small peptides that act as hormones of the immune system, affect cells throughout the body in a variety of different ways. These cellular signaling molecules often have synergistic or opposing effects on various cell types and often different cytokines have overlapping activities. There is great advantage, therefore, to be able to assess a pattern of cytokine responses in certain inflammatory, autoimmune, transplant or immunodeficiency states. This is one of the major advantages of the new particle-based flow cytometric assays, which have become available. We have employed such assays to analyze up to 10 different cytokines in cultured supernatants of stimulated mononuclear cells and in as little as 75 microL of serum from patients with a variety of different disorders. In developing these assays and validating them for use in our esoteric reference laboratory (ARUP Laboratories), we have found that a variety of heterophile antibodies can lead to both false positive and false negative results. This review will describe the development of our multi-analyte cytokine assays and document the interference derived from heterophile antibodies. Lastly, we will point out various procedures that we have utilized to include internal controls directly in the assays, which allow one to routinely detect these interfering antibodies, as well as methods we have developed to circumvent the interference posed by these antibodies.     

Avoidance and suppression of plant defenses by herbivores and pathogens

Plants are nutritious and hence herbivores and phytopathogens have specialized to attack and consume them. In turn, plants have evolved adaptations to detect and withstand these attacks. Such adaptations we call ‘defenses’ and they can operate either directly between the plant and the plant consumer or indirectly i.e. when taking effect via other organisms such as predators and parasitoids of herbivores. Plant defenses put selection pressure on plant-consumers and, as a result, herbivores and pathogens have evolved counter-adaptations to avoid, resist, or manipulate plant defenses. Here we review how plant consumers have adapted to cope with plant defenses and we will put special emphasis on the phenomenon of suppression of plant defenses.     

The PARLance of Parkinson disease

Mitochondrial biology has recently emerged as a key regulatory event in Parkinson disease (PD). Notably, defects in the clearance of damaged mitochondria, termed mitophagy, have been recently highlighted as a possible mechanistic explanation for neuronal loss. We have recently identified the mitochondrial rhomboid, termed PARL, as a regulator of the cells mitophagic response. Further, we have identified PD-linked mutations at a functional site in the PARL gene. Here we discuss the benefit of combining molecular genetic and cell biology approaches in understanding human disease.     

The PARLance of Parkinson disease

Mitochondrial biology has recently emerged as a key regulatory event in Parkinson disease (PD). Notably, defects in the clearance of damaged mitochondria, termed mitophagy, have been recently highlighted as a possible mechanistic explanation for neuronal loss. We have recently identified the mitochondrial rhomboid, termed PARL, as a regulator of the cells mitophagic response. Further, we have identified PD-linked mutations at a functional site in the PARL gene. Here we discuss the benefit of combining molecular genetic and cell biology approaches in understanding human disease.     

Analysis of a model for transmitter kinetics

Neural transmitters can generally exist in several states: stored, released, in combination with receptors, and recycling to storage. A set of equations is proposed and analyzed for such a system. We have considered boundedness and stability of solutions, and we have discussed physiological effects such as response saturation and adaptation. We have investigated the effects of the model parameters on system behavior and we have indicated how the model can be extended to include phenomena such as transmitter mobilization, modulation if its release and receptor desensitization.     

Corrected estimator of sensitive population proportion using unknown repeated trials in the unrelated question randomized response model

In this paper, we have pointed out a major mistake in the research paper of Singh and Mathur [(2004). Unknown repeated trials in the unrelated question randomized response model, Biometrical Journal, 46:375–378]. We have corrected this mistake and proposed the corresponding corrected estimator of sensitive population proportion. Furthermore, we have obtained the variance of our proposed estimator. Likewise, Singh and Mathur, we have also compared the variance of our proposed estimator with that of the Greenberg et al.’s estimator theoretically as well as numerically.     

Experimental evidence of cost of lactation in a low risk environment for a long-lived mammal

In a previous experiment we have documented that organisms adopt a risk-sensitive reproductive allocation when summer reproductive investment competes with survival in the coming winter ( Bårdsen et al. 2008 ). This tradeoff is present through autumn female body mass, which acts as an insurance against unpredictable winter environmental conditions. We tested this hypothesis experimentally on female reindeer experiencing stable and benign winter feeding conditions. Additional supplementary feeding and removal of newborns represented two sets of experimental manipulations. Females in the supplementary feeding group increased more in winter body mass relative to control females. This manipulation, however, did not have any effect on summer body mass development for neither females nor offspring, but we found a positive effect of feeding on offspring birth mass for smaller females. In contrast, offspring removal did have a positive effect on summer body mass development as females in this group were larger in the autumn relative to control females. In essence, we documented two immediate effects as: (1) supplementary feeding did have a positive effect on spring body mass for smaller females; and (2) offspring removal did increase the female summer somatic growth as this had a positive effect on female autumn body mass. Additionally, we tested for lagged effects, but we could not document any biologically significant effects of neither manipulation in the coming spring. The fact that we only found rather weak effects of both manipulations was as expected for risk sensitive individuals experiencing benign environmental conditions over many years.     

The welfare of fish

Our interactions with fish cover a wide range of activities including enjoying them as pets to consuming them as food. I propose that we confine the consideration of the welfare of fish to their physiology, and not join the discussion on whether fish can feel pain and suffering, as humans. A significant proportion of the papers on animal welfare center on whether non-human animals can feel pain, and suffer as humans. This is a question that never can be answered unequivocally. The premise of the present paper is that we have an ethical responsibility to respect the life and wellbeing of all organisms. Thus, we should concentrate on the behavioural, physiological, and cellular indicators of their well-being and attempt to minimize a state of stress in the animals that we have in our care or influence.     

Identification of adeno-associated virus contamination in cell and virus stocks by PCR

To further understand the biology of adeno-associated virus (AAV) and identify the presence of AAV in laboratory samples, we have developed a sensitive PCR-based assay using degenerate primers based on the sequence of seven diverse AAV isolates. Using these primers, we can detect free virus in viral stocks, cleared cell lysate, as well as in latently infected cells. The method can detect as little as 10 viral copies/microL of sample and can be adapted for high-throughput screening technology. With this method, we have also detected a new AAV isolate from a stock of bovine adenovirus.     

Live-cell imaging of tumor proteolysis: Impact of cellular and non-cellular microenvironment

Our laboratory has had a longstanding interest in how the interactions between tumors and their microenvironment affect malignant progression. Recently, we have focused on defining the proteolytic pathways that function in the transition of breast cancer from the pre-invasive lesions of ductal carcinoma in situ (DCIS) to invasive ductal carcinomas (IDCs). We use live-cell imaging to visualize, localize and quantify proteolysis as it occurs in real-time and thereby have established roles for lysosomal cysteine proteases both pericellularly and intracellularly in tumor proteolysis. To facilitate these studies, we have developed and optimized 3D organotypic co-culture models that recapitulate the in vivo interactions of mammary epithelial cells or tumor cells with stromal and inflammatory cells. Here we will discuss the background that led to our present studies as well as the techniques and models that we employ. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.     

Design at the atomic level: generation of novel hybrid biaryloxazolidinones as promising new antibiotics

From the X-ray crystal structures of linezolid and the non-selective antibiotic sparsomycin, we have derived a new family of hybrid oxazolidinones. From this initial compound set we have developed a new biaryloxazolidinone scaffold that shows both potent antimicrobial activity as well as selective inhibition of ribosomal translation. The synthesis of these compounds is outlined.     

Mucosal delivery of therapeutic and prophylactic molecules using lactic acid bacteria

Studies of lactic acid bacteria (LAB) as delivery vehicles have focused mainly on the development of mucosal vaccines, with much effort being devoted to the generation of genetic tools for antigen expression in different bacterial locations. Subsequently, interleukins have been co-expressed with antigens in LAB to enhance the immune response that is raised against the antigen. LAB have also been used as a delivery system for a range of molecules that have different applications, including anti-infectives, therapies for allergic diseases and therapies for gastrointestinal diseases. Now that the first human trial with a Lactococcus strain that expresses recombinant interleukin-10 has been completed, we discuss what we have learnt, what we do not yet understand and what the future holds for therapy and prophylaxis with LAB.     

Characterization of pancreastatin receptors and signaling in adipocyte membranes.

Pancreastatin (PST), a chromogranin A derived peptide with an array of effects in different tissues, has a role as a counterregulatory hormone of insulin action in hepatocytes and adipocytes, regulating glucose, lipid and protein metabolism. We have previously characterized PST receptors and signaling in rat hepatocytes, in which PST functions as a calcium-mobilizing hormone. In the present work we have studied PST receptors as well as the signal transduction pathways generated upon PST binding in adipocyte membranes. First, we have characterized PST receptors using radiolabeled PST as a ligand. Analysis of binding data indicated the existence of one class of binding sites, with a B(max) of 5 fmol/mg of protein and a K(d) of 1 nM. In addition, we have studied the G protein system that couples the PST receptor by gamma-(35)S-GTP binding studies. We have found that two G protein systems are involved, pertussis toxin-sensitive and -insensitive respectively. Specific anti-G protein alpha subtype sera were used to block the effect of pancreastatin receptor activation. Galpha(q/11) and to a lesser extent Galpha(i1,2) are activated by PST in rat adipocyte membranes. On the other hand, adenylate cyclase activity was not affected by PST. Finally, we have studied the specific phospholipase C isoform that is activated in response to PST. We have found that PST receptor is coupled to PLC-beta(3) via Galpha(q/11) activation in adipocyte membranes.     

Rapid identification of gelatin and casein hydrolysis using TCA

Using TCA as the developing agent we have identified the hydrolysis of gelatin and casein within 3 h. When compared with conventional gelatin and casein hydrolysis techniques we have found the results of the TCA enhancement to be more rapid and sensitive than the conventional methods.     

Live-cell analysis of a green fluorescent protein-tagged herpes simplex virus infection

Many stages of the herpes simplex virus maturation pathway have not yet been defined. In particular, little is known about the assembly of the virion tegument compartment and its subsequent incorporation into maturing virus particles. Here we describe the construction of a herpes simplex virus type 1 (HSV-1) recombinant in which we have replaced the gene encoding a major tegument protein, VP22, with a gene expressing a green fluorescent protein (GFP)-VP22 fusion protein (GFP-22). We show that this virus has growth properties identical to those of the parental virus and that newly synthesized GFP-22 is detectable in live cells as early as 3 h postinfection. Moreover, we show that GFP-22 is incorporated into the HSV-1 virion as efficiently as VP22, resulting in particles which are visible by fluorescence microscopy. Consequently, we have used time lapse confocal microscopy to monitor GFP-22 in live-cell infection, and we present time lapse animations of GFP-22 localization throughout the virus life cycle. These animations demonstrate that GFP-22 is present in a diffuse cytoplasmic location when it is initially expressed but evolves into particulate material which travels through an exclusively cytoplasmic pathway to the cell periphery. In this way, we have for the first time visualized the trafficking of a herpesvirus structural component within live, infected cells.     

Review of plant biogeographic studies in Brazil

Molecular phylogenetic studies have become a major area of interest in plant systematics, and their impacts on historical biogeographic hypotheses are not to be disregarded. In Brazil, most historical biogeographic studies have relied on animal phylogenies, whereas plant biogeographic studies have largely lacked a phylogenetic component, having a limited utility for historical biogeography. That country, however, is of great importance for most biogeographic studies of lowland tropical South America, and it includes areas from a number of biogeographic regions of the continent. Important biogeographic reports have been published as part of phylogenetic studies, taxonomic monographs, and regional accounts for small areas or phytogeographic domains, but the available information is subsequently scattered and sometimes hard to find. In this paper we review some relevant angiosperm biogeographic studies in Brazil. Initially we briefly discuss the importance of other continents as source areas for the South American flora. Then we present a subdivision of Brazil into phytogeographic domains, and we cite studies that have explored the detection of biogeographic units （areas of endemism） and how they are historically related among those domains. Examples of plant taxa that could be used to test some biogeographic hypotheses are provided throughout, as well as taxa that exemplify several patterns of endemism and disjunction in the Brazilian angiosperm flora.     

Hybrid mouse diversity panel: a panel of inbred mouse strains suitable for analysis of complex genetic traits

We have developed an association-based approach using classical inbred strains of mice in which we correct for population structure, which is very extensive in mice, using an efficient mixed-model algorithm. Our approach includes inbred parental strains as well as recombinant inbred strains in order to capture loci with effect sizes typical of complex traits in mice (in the range of 5?% of total trait variance). Over the last few years, we have typed the hybrid mouse diversity panel (HMDP) strains for a variety of clinical traits as well as intermediate phenotypes and have shown that the HMDP has sufficient power to map genes for highly complex traits with resolution that is in most cases less than a megabase. In this essay, we review our experience with the HMDP, describe various ongoing projects, and discuss how the HMDP may fit into the larger picture of common diseases and different approaches.