Immune mechanisms in the pathogenesis of idiopathic inflammatory myopathies

Idiopathic inflammatory myopathies (IIMs), comprising polymyositis, dermatomyositis, and inclusion-body myositis, are characterized by inflammatory cell infiltrates in skeletal muscle tissue, muscle weakness, and muscle fatigue. The cellular infiltrates often consist of T lymphocytes and macrophages but also, in some cases, B lymphocytes. Emerging data have led to improved phenotypic characterization of the inflammatory cells, including their effector molecules, in skeletal muscle, peripheral blood, and other organs that are frequently involved, such as skin and lungs. In this review we summarize the latest findings concerning the role of T lymphocytes, B lymphocytes, dendritic cells, and other antigen-presenting cells in the pathophysiology of IIMs.     

To be or not to be in the nucleolus

Compartmentalization has long been known to have a key role in regulation of cellular processes. By keeping enzymes and regulatory complexes in compartments where the delivery of substrate or exit of product is controlled, competing reactions can occur simultaneously in different parts of the cell. Moreover, spatial confinement facilitates the working of molecules participating in reaction chains and is crucial for coupling unfavourable with energetically favourable chemical reactions. Although in many cases intracellular compartmentalization relies on boundaries imposed by membranes, several non-membrane-bounded compartments exist in eukaryotic cells. One of these, the nucleolus, has recently attracted much attention. The emerging view is that molecular confinement in the nucleolus actively contributes to the control of cellular survival and proliferation.     

Immunoglobulin-secreting cells of maternal origin can be detected in B cell-deficient mice

It is well known that the transfer of immunoglobulins (Igs) from mother to young via milk contributes to the offspring's immune defense. The present study suggests that not only is IgG transmitted to progeny, but that functional maternal Ig-secreting cells (or B cells) can also be transferred to the neonate. We have used B cell-deficient (micro(-/-)) mice and found that a high proportion of them obtain long-lasting, partial reconstitution of their serum Ig levels if born to micro(+/-) mothers. In some of these serum IgG-positive micro(-/-) mice, Ig-secreting cells were detected in spleen and bone marrow. To ensure that cells of maternal origin were present in the progeny, micro(-/-) offspring born to micro(+/-) dams transgenic for green fluorescent protein (GFP) were used. In spleens and bone marrow from some of these micro(-/-)GFP(-/-) offspring, GFP-positive cells were detected, which demonstrated that cells of maternal origin could infiltrate the progeny. In addition, splenic Ig-secreting cells were detected in micro(-/-) mice that were born to micro(-/-) dams and transferred to a lactating micro(+/+) foster dam at birth. This indicates that maternal Ig-secreting cells can be transferred postnatally via milk.     

Trypanosoma vivax in Glossina palpalis gambiensis do not appear to affect feeding behaviour, longevity or reproductive performance of the vector

Feeding behaviour of Glossina palpalis gambiensis Vanderplank infected with Trypanosoma vivax Ziemann was studied and compared with that of uninfected control tsetse. The parameters measured were: total number of probes into the ear-skin of rabbits; rate of bloodmeal engorgement; weight of freshly ingested blood; survival; and mean weight of pupae. The results showed that the rosettes of T.vivax parasites in the labrum did not interfere with the feeding behaviour of the vectors. Furthermore, mean survival of T. vivax-infected males was significantly higher (82.2 +/- 4.2 days) compared with that of uninfected ones (70.5 +/- 3.1 days). However, with the female tsetse, mean survival of those infected was lower (98.8 +/- 4.0 days) compared to the uninfected controls (102.2 +/- 5.6 days), but the difference was not significant. A few infected males and females lived a little longer than the uninfected ones. Fecundity of the female tsetse remained unaffected by the infection, and furthermore the mean weight of pupae from the infected females was not significantly different from that of pupae from the uninfected control group. Thus the physiology of pregnant female tsetse in terms of nourishment of intra-uterine larva was unaffected by T.vivax infection. Two successive probes into the skin of two different goats followed by feeding on a third goat by each of four infected tsetse resulted in successful transmission of the infection to eleven out of twelve goats. Thus probing alone into the skin of this host can result in the transmission of T.vivax infection.     

Direct effects of the pathogenic mutation on satellite cell function in muscular dystrophy

Skeletal muscle is maintained and repaired by resident stem cells called muscle satellite cells, but there is a gradual failure of this process during the progressive skeletal muscle weakness and wasting that characterises muscular dystrophies. The pathogenic mutation causes muscle wasting, but in conditions including Duchenne muscular dystrophy, the mutant gene is not expressed in satellite cells, and so muscle maintenance/repair is not directly affected. The chronic muscle wasting, however, produces an increasingly hostile micro-environment in dystrophic muscle. This probably combines with excessive satellite cell use to eventually culminate in an indirect failure of satellite cell-mediated myofibre repair. By contrast, in disorders such as Emery-Dreifuss muscular dystrophy, the pathogenic mutation not only instigates muscle wasting, but could also directly compromise satellite cell function, leading to less effective muscle homeostasis. This may again combine with excessive use and a hostile environment to further compromise satellite cell performance. Whichever the mechanism, the ultimate consequence of perturbed satellite cell activity is a chronic failure of myofibre maintenance in dystrophic muscle. Here, we review whether the pathogenic mutation can directly contribute to satellite cell dysfunction in a number of muscular dystrophies.     

Targeted deletion of the muscular dystrophy gene myotilin does not perturb muscle structure or function in mice

Myotilin, palladin, and myopalladin form a novel small subfamily of cytoskeletal proteins that contain immunoglobulin-like domains. Myotilin is a thin filament-associated protein localized at the Z-disk of skeletal and cardiac muscle cells. The direct binding to F-actin, efficient cross-linking of actin filaments, and prevention of induced disassembly of filaments are key roles of myotilin that are thought to be involved in structural maintenance and function of the sarcomere. Missense mutations in the myotilin-encoding gene cause dominant limb girdle muscular dystrophy type 1A and spheroid body myopathy and are the molecular defect that can cause myofibrillar myopathy. Here we describe the generation and analysis of mice that lack myotilin, myo(-/-) mice. Surprisingly, myo(-/-) mice maintain normal muscle sarcomeric and sarcolemmal integrity. Also, loss of myotilin does not cause alterations in the heart or other organs of newborn or adult myo(-/-) mice. The mice develop normally and have a normal life span, and their muscle capacity does not significantly differ from wild-type mice even after prolonged physical stress. The results suggest that either myotilin does not participate in muscle development and basal function maintenance or other proteins serve as structural and functional compensatory molecules when myotilin is absent.     

Immature euphausiids do not appear to be prey for humpback whales (Megaptera novaeangliae) during spring and summer in Southeast Alaska

Humpbacks whales (Megaptera novaeangliae) have shown a remarkable recovery in the North Pacific, raising concerns regarding their impact on marine communities. In Southeast Alaska, humpbacks feed heavily on euphausiids; however, it remains unclear whether they target immature individuals despite evidence that they do so elsewhere. I evaluate the hypothesis that humpbacks target immature euphausiids in late spring‐summer in Southeast Alaska. Plankton samples were collected at random sites (n = 44) and near whales (n = 53) between 8 June and 9 September 2008 in Frederick Sound and Stephens Passage. The proportion of samples containing immature euphausiids, and immature euphausiid abundance within those samples, were compared between the two sample types. Similar analyses were conducted for adult euphausiids (prey) and calanoid copepods (nonprey) for comparison. I found no statistical difference between the whale and random samples with respect to the occurrence or numerical density of immature euphausiids, which is consistent with the hypothesis that whales did not target them in 2008. Smaller size, insufficient numerical densities and lower energy density of immature euphausiids are suggested as possible reasons. These findings can assist in resolving regional humpback abundance and distribution patterns, and can contribute to an understanding of the trophic interactions characterizing the local ecosystem.     

Cytokines in the muscle tissue of idiopathic inflammatory myopathies: implications for immunopathogenesis and therapy

The inflammatory myopathies (IM), dermatomyositis (DM), polymyositis (PM) and idiopathic inclusion body myositis (IBM) are acquired immune-mediated myopathies. About their pathogenesis and etiology no definitive insights are available yet. Here we present a review of cytokine studies in IM. Combined with cellular immunohistochemical findings a model is presented describing a common mechanism of immune activation in IM. This model is based on a "hit" triggering local cytokine production with dominance of pro-inflammatory cytokines, like IFN-gamma and Th1-mediated activities. The altered Th1-Th2 balance necessitates detection of the anti-inflammatory arm of immune activation, which includes Th2-derived IL-4, IL-1, and Th3/Tr1 derived IL-10 and TGF-beta. Redirection of the ratio provides targets for novel immunotherapy by direct inhibition of the IFN-gamma-mediated Th1 response, stimulation of Th3/Tr1, or IL-4-secreting Th2-cells, negative feedback inhibition with IFN-beta and IFN-gamma and inactivation of MHC molecules.     

To be or not to be: The double-edged sword roles of liver progenitor cells

Given the liver's remarkable and unique regenerative capacity, researchers have long focused on liver progenitor cells (LPCs) and liver cancer stem cells (LCSCs). LPCs can differentiate into both hepatocytes and cholangiocytes. However, the mechanism underlying cell conversion and its distinct contribution to liver homeostasis and tumorigenesis remain unclear. In this review, we discuss the complicated conversions involving LPCs and LCSCs. As the critical intermediate state in malignant transformation, LPCs play double-edged sword roles. LPCs are not only involved in hepatic wound-healing responses by supplementing liver cells and bile duct cells in the damaged liver but may transform into LCSCs under dysregulation of key signaling pathways, resulting in refractory malignant liver tumors. Because LPC lineages are temporally and spatially dynamic, we discuss crucial LPC subgroups and summarize regulatory factors correlating with the trajectories of LPCs and LCSCs in the liver tumor microenvironment. This review elaborates on the double-edged sword roles of LPCs to help understand the liver's regenerative potential and tumor heterogeneity. Understanding the sources and transformations of LPCs is essential in determining how to exploit their regenerative capacity in the future.     

Acrosin does not appear to be bound to the inner acrosomal membrane of bull spermatozoa.

Ferritin-conjugated soybean trypsin inhibitor was used for the ultrastructural localization of acrosin in bull spermatozoa following acrosomal disruption. The ferritin label was observed in the anterior segment of the acrosome in disrupted cells only. Emptied acrosomes were labeled, mostly on the external surface of their outer membrane. Labeling was also found on the material bound to detached acrosomal caps. However, at no time could the ferritin label be found on the inner acrosomal membrane. It is concluded that acrosin activity is not present on the inner acrosomal membrane but is lost from the acrosomal matrix as the acrosomal reaction proceeds.     

Virilization of the male pouch young of the tammar wallaby does not appear to be mediated by plasma testosterone or dihydrotestosterone.

Virilization of the male urogenital tract of all mammals, including marsupials, is mediated by androgenic hormones secreted by the testes. We have previously demonstrated profound sexual dimorphism in the concentrations of gonadal androgens in pouch young of the tammar wallaby Macropus eugenii during the interval when the urogenital sinus virilizes. To provide insight into the mechanisms by which androgens are transported from the testes to the target tissues, we measured testosterone and dihydrotestosterone in plasma pools from tammar pouch young from the day of birth to Day 150. Plasma testosterone levels were measurable (0.5-2 ng/ml) at all times studied, but there were no differences between males and females. These low concentrations of plasma testosterone appear to be derived from the adrenal glands and not the testes. Plasma dihydrotestosterone levels in plasma pools from these animals were also low and not sexually dimorphic. We conclude that virilization of the male urogenital tract cannot be explained by the usual transport of testosterone or dihydrotestosterone in plasma but may be mediated by the direct delivery of androgens to the urogenital tract via the Wolffian ducts. Alternatively, circulating prohormones may be converted to androgens in target tissues.     

A comprehensive review of epinephrine in the finger: to do or not to do.

The prohibition against the use of local anesthetics with epinephrine for digital blocks or infiltration is an established surgical tradition. The present article provides a comprehensive review of all reported digital necrotic and ischemic complications with epinephrine in the digits in an effort to understand whether the current prohibition is based on documented reports. A comprehensive review of articles showing the successful use of local anesthetic with epinephrine in the digits is presented.A review of Index Medicus from 1880 to 1966 and a computer review of the National Library of Medicine database from 1966 to 2000 were performed using multiple keywords. Selected major textbooks from 1900 to 2000 were also reviewed.A total of 48 cases of digital gangrene after anesthetic blocks (mostly using cocaine or procaine) have been reported in the world literature. Only 21 cases involved the use of epinephrine; 17 involved an unknown concentration based on manual dilution. Multiple other concurrent conditions (hot soaks, tight tourniquets, and infection) existed in these case reports, making it difficult to determine the exact cause of the tissue insult. There have been no case reports of digital gangrene using commercial lidocaine with epinephrine (introduced in 1948). Multiple studies involving thousands of patients support the premise that the use of lidocaine with epinephrine is safe in the digits.An extensive literature review failed to provide consistent evidence that our current preparations of local anesthesia with epinephrine cause digital necrosis, although not all complications are necessarily reported. However, as with all techniques, caution is necessary to balance the risks of this technique with the dangers of mechanical tourniquets and upper extremity block anesthesia.     

Motoneurons and oligodendrocytes are sequentially generated from neural stem cells but do not appear to share common lineage-restricted progenitors in vivo

Olig gene expression is proposed to mark the common progenitors of motoneurons and oligodendrocytes. In an attempt to further dissect the in vivo lineage relationships between motoneurons and oligodendrocytes, we used a conditional cell-ablation approach to kill Olig-expressing cells. Although differentiated motoneurons and oligodendrocytes were eliminated, our ablation study revealed a continuous generation and subsequent death of their precursors. Most remarkably, a normal number of oligodendrocyte precursors are formed at day 12 of mouse development, after all motoneuron precursors have been killed. The data presented herein supports a sequential model in which motoneuron and oligodendrocyte precursors are sequentially generated in vivo from neuroepithelial stem cells, but do not share a common lineage-restricted progenitor.     

Dual role of CDKs in DNA repair: to be, or not to be

The maintenance of genome integrity is essential for the regulation of cell proliferation and differentiation. DNA must be accurately duplicated and segregated to daughter cells at cell division, a process that is primarily regulated by cyclin-dependent kinases (CDKs). During cell growth, however, it is inevitable that DNA breaks will occur due to endogenous and exogenous stresses. Interestingly, there is increasing evidence that the catalytic activities of CDKs play critical roles in the DNA damage response, especially in the case of damage repaired by the homologous recombination (HR) pathway. In this review, we outline current knowledge of CDK regulation and its roles both in the unperturbed cell cycle and in DNA damage responses, and discuss the physiological roles of CDKs in HR repair.