Hemoptysis: Diagnosis and Management

Hemoptysis is one of the most important symptoms of cardiopulmonary disease—first, because bleeding even in small amounts may indicate the presence of such serious diseases as bronchogenic carcinoma or active tuberculosis, and second, because untreated massive hemorrhage is associated with a high mortality rate. The cause of hemoptysis may be suggested by the history, physical examination or chest x-ray findings, but often diagnostic procedures such as bronchoscopy, bronchography and pulmonary angiography are needed for definitive diagnosis. The importance of early localization of the bleeding site and surgical intervention in patients with massive hemoptysis is stressed.     

Modeling a disease-correlated tubulin mutation in budding yeast reveals insight into MAP-mediated dynein function

Mutations in the genes that encode α- and β-tubulin underlie many neurological diseases, most notably malformations in cortical development. In addition to revealing the molecular basis for disease etiology, studying such mutations can provide insight into microtubule function and the role of the large family of microtubule effectors. In this study, we use budding yeast to model one such mutation—Gly436Arg in α-tubulin, which is causative of malformations in cortical development—in order to understand how it impacts microtubule function in a simple eukaryotic system. Using a combination of in vitro and in vivo methodologies, including live cell imaging and electron tomography, we find that the mutant tubulin is incorporated into microtubules, causes a shift in α-tubulin isotype usage, and dramatically enhances dynein activity, which leads to spindle-positioning defects. We find that the basis for the latter phenotype is an impaired interaction between She1—a dynein inhibitor—and the mutant microtubules. In addition to revealing the natural balance of α-tubulin isotype utilization in cells, our results provide evidence of an impaired interaction between microtubules and a dynein regulator as a consequence of a tubulin mutation and sheds light on a mechanism that may be causative of neurodevelopmental diseases.     

Almost 20 years of Neanderthal palaeogenetics: adaptation,admixture, diversity,demography and extinction

Nearly two decades since the first retrieval of Neanderthal DNA, recent advances in next-generation sequencing technologies have allowed the generation of high-coverage genomes from two archaic hominins, a Neanderthal and a Denisovan, as well as a complete mitochondrial genome from remains which probably represent early members of the Neanderthal lineage. This genomic information, coupled with diversity exome data from several Neanderthal specimens is shedding new light on evolutionary processes such as the genetic basis of Neanderthal and modern human-specific adaptations—including morphological and behavioural traits—as well as the extent and nature of the admixture events between them. An emerging picture is that Neanderthals had a long-term small population size, lived in small and isolated groups and probably practised inbreeding at times. Deleterious genetic effects associated with these demographic factors could have played a role in their extinction. The analysis of DNA from further remains making use of new large-scale hybridization-capture-based methods as well as of new approaches to discriminate contaminant DNA sequences will provide genetic information in spatial and temporal scales that could help clarify the Neanderthal''s—and our very own—evolutionary history.     

The Role of Percutaneous Lung Biopsy in the Workup of a Solitary Pulmonary Nodule

As the technique of percutaneous lung biopsy continues to evolve, it offers an increasingly accurate method of establishing the malignancy or benignity of a solitary pulmonary nodule. There are relatively few contraindications to the procedure, and the complications—primarily pneumothorax and hemoptysis—generally resolve without therapy. Transthoracic needle aspiration has an important role in the workup for a “coin lesion.” Other elements of the diagnostic workup—particularly the history, a chest roentgenogram, computed tomography, sputum cytology, and transbronchial brush biopsy—may either add to or substitute for a transthoracic needle aspiration biopsy. An algorithm can be used to guide the diagnostic approach to a solitary pulmonary nodule.     

A helping hand: How vinculin contributes to cell-matrix and cell-cell force transfer

Vinculin helps cells regulate and respond to mechanical forces. It is a scaffolding protein that tightly regulates its interactions with potential binding partners within adhesive structures—including focal adhesions that link the cell to the extracellular matrix and adherens junctions that link cells to each other—that physically connect the force-generating actin cytoskeleton (CSK) with the extracellular environment. This tight control of binding partner interaction—mediated by vinculin''s autoinhibitory head–tail interaction—allows vinculin to rapidly interact and detach in response to changes in the dynamic forces applied through the cell. In doing so, vinculin modulates the structural composition of focal adhesions and the cell''s ability to generate traction forces and adhesion strength. Recent evidence suggests that vinculin plays a similar role in regulating the fate and function of cell–cell junctions, further underscoring the importance of this protein. Using our lab''s recent work as a starting point, this commentary explores several outstanding questions regarding the nature of vinculin activation and its function within focal adhesions and adherens junctions.     

PARENT DEVELOPMENT

Today''s parents tend to be overwhelmed with advice from many sources. In his role as family counselor, the pediatrician must understand and consider the emotional development of parents in relation to their child''s development; otherwise, his advice and counsel do not “take” and he becomes tired and frustrated and angry.Parents progress through definite stages of development: Stage 1: Learning the cues—the struggle of the parents to interpret the infant''s needs. Stage 2: Learning to accept growth and development—the parent learning to accept some loss of control of the toddler. Stage 3: Learning to separate—the parent learning to allow the child to develop independently. Stage 4: Learning to accept rejection, without deserting—the struggle of the parents not to intrude and yet to be there when needed. Stage 5: Learning to build a new life having been thoroughly discredited by one''s teenager—the parent learning to live independently while the teenager struggles to develop his own identity.The pediatrician who is accepting, sensitive and a good listener and who keeps in mind that parents as well as children have capacities for growth and development, will be a potent factor in promoting good parent-child relationships and many times more effective in dealing with the child in health and disease.     

BicaudalD Actively Regulates Microtubule Motor Activity in Lipid Droplet Transport

Background

A great deal of sub-cellular organelle positioning, and essentially all minus-ended organelle transport, depends on cytoplasmic dynein, but how dynein''s function is regulated is not well understood. BicD is established to play a critical role in mediating dynein function—loss of BicD results in improperly localized nuclei, mRNA particles, and a dispersed Golgi apparatus—however exactly what BicD''s role is remains unknown. Nonetheless, it is widely believed that BicD may act to tether dynein to cargos. Here we use a combination of biophysical and biochemical studies to investigate BicD''s role in lipid droplet transport during Drosophila embryogenesis.

Methodology/Principal Findings

Functional loss of BicD impairs the embryo''s ability to control the net direction of droplet transport; the developmentally controlled reversal in transport is eliminated. We find that minimal BicD expression (near-BicD^null) decreases the average run length of both plus and minus end directed microtubule (MT) based transport. A point mutation affecting the BicD N-terminus has very similar effects on transport during cellularization (phase II), but in phase III (gastrulation) motion actually appears better than in the wild-type.

Conclusions/Significance

In contrast to a simple static tethering model of BicD function, or a role only in initial dynein recruitment to the cargo, our data uncovers a new dynamic role for BicD in actively regulating transport. Lipid droplets move bi-directionally, and our investigations demonstrate that BicD plays a critical—and temporally changing—role in balancing the relative contributions of plus-end and minus-end motors to control the net direction of transport. Our results suggest that while BicD might contribute to recruitment of dynein to the cargo it is not absolutely required for such dynein localization, and it clearly contributes to regulation, helping activation/inactivation of the motors.     

Physicians' Own Health—Some Advice for the Advisors

Information about physicians'' health and health practices is sparse and scattered. With a few exceptions, however—notably suicide and substance abuse—it appears that physicians'' health and health-promotion activities are at least similar to those of the general public. In some areas, such as smoking cessation, physicians have far outstripped the general public. As physicians gain more insight into their own health and health habits, advice to patients can be realistic and effective. Indeed, several personal health activities, including immunization, have direct, salutary impacts on patient care. Physicians should analyze and change their own health practices as indicated and pay special attention to “high yield” health habits, such as seat-belt use.     

PULMONARY OPERATIONS IN EMPHYSEMATOUS PATIENTS

Although emphysema itself is a disease of the entire lungs and so is not amenable to surgical therapy, there are many conditions in emphysematous patients in which surgical operation can be quite helpful—for example, some complications of emphysema and some conditions not etiologically related to emphysema but affecting the lungs. Among these conditions are infectious diseases (pneumonia, bronchiectasis, tuberculosis and infected bullae) and other conditions such as spontaneous pneumothorax, the presence of space-occupying bullae and carcinoma.The surgical treatment required may range from suction or drainage to wide resection.     

Genomic imprinting and the units of adaptation

Two guiding principles identify which biological entities are able to evolve adaptations. Williams'' principle holds that, in order for an entity to evolve adaptations, there must be selection between such entities. Maynard Smith''s principle holds that, in order for an entity to evolve adaptations, selection within such entities must be absent or negligible. However, although the kinship theory of genomic imprinting suggests that parent-of-origin-specific gene expression evolves as a consequence of natural selection acting between—rather than within—individuals, it evades adaptive interpretation at the individual level and is instead viewed as an outcome of an intragenomic conflict of interest between an individual''s genes. Here, I formalize the idea that natural selection drives intragenomic conflicts of interest between genes originating from different parents. Specifically, I establish mathematical links between the dynamics of natural selection and the idea of the gene as an intentional, inclusive-fitness-maximizing agent, and I clarify the role that information about parent of origin plays in mediating conflicts of interest between genes residing in the same genome. These results highlight that the suppression of divisive information may be as important as the suppression of lower levels of selection in maintaining the integrity of units of adaptation.     

Occupational Skin Diseases in the San Francisco Bay Area

From answers by one-third of the practicing dermatologists in the San Francisco Bay Area to a questionnaire on occupational skin diseases, contact dermatitis due to irritants and sensitizers was found to rank first. Poison oak, which is the leading reported cause on “Doctor''s First Report of Work Injury” received by the California Department of Industrial Relations, was sixth on the list of the survey, trailing solvents, cleansing agents, petroleum products and epoxy resins. A history of atopic dermatitis was often noted in current cases of occupational diseases of the skin.Avoidance of exposure or limiting the contact with pathogenic substances—through engineering changes, observation of working conditions by physicians, education of workers—appeared to be the best preventive measures.     

TNF-α synergises with IFN-γ to induce caspase-8-JAK1/2-STAT1-dependent death of intestinal epithelial cells

Rewiring of host cytokine networks is a key feature of inflammatory bowel diseases (IBD) such as Crohn’s disease (CD). Th1-type cytokines—IFN-γ and TNF-α—occupy critical nodes within these networks and both are associated with disruption of gut epithelial barrier function. This may be due to their ability to synergistically trigger the death of intestinal epithelial cells (IECs) via largely unknown mechanisms. In this study, through unbiased kinome RNAi and drug repurposing screens we identified JAK1/2 kinases as the principal and nonredundant drivers of the synergistic killing of human IECs by IFN-γ/TNF-α. Sensitivity to IFN-γ/TNF-α-mediated synergistic IEC death was retained in primary patient-derived intestinal organoids. Dependence on JAK1/2 was confirmed using genetic loss-of-function studies and JAK inhibitors (JAKinibs). Despite the presence of biochemical features consistent with canonical TNFR1-mediated apoptosis and necroptosis, IFN-γ/TNF-α-induced IEC death was independent of RIPK1/3, ZBP1, MLKL or caspase activity. Instead, it involved sustained activation of JAK1/2-STAT1 signalling, which required a nonenzymatic scaffold function of caspase-8 (CASP8). Further modelling in gut mucosal biopsies revealed an intercorrelated induction of the lethal CASP8-JAK1/2-STAT1 module during ex vivo stimulation of T cells. Functional studies in CD-derived organoids using inhibitors of apoptosis, necroptosis and JAKinibs confirmed the causative role of JAK1/2-STAT1 in cytokine-induced death of primary IECs. Collectively, we demonstrate that TNF-α synergises with IFN-γ to kill IECs via the CASP8-JAK1/2-STAT1 module independently of canonical TNFR1 and cell death signalling. This non-canonical cell death pathway may underpin immunopathology driven by IFN-γ/TNF-α in diverse autoinflammatory diseases such as IBD, and its inhibition may contribute to the therapeutic efficacy of anti-TNFs and JAKinibs.Subject terms: Necroptosis, Cell death and immune response, Interferons, Tumour-necrosis factors, Crohn''s disease     

Sexual antagonism for resistance and tolerance to infection in Drosophila melanogaster

A critical task in evolutionary genetics is to explain the persistence of heritable variation in fitness-related traits such as immunity. Ecological factors can maintain genetic variation in immunity, but less is known about the role of other factors, such as antagonistic pleiotropy, on immunity. Sexually dimorphic immunity—with females often being more immune-competent—may maintain variation in immunity in dioecious populations. Most eco-immunological studies assess host resistance to parasites rather than the host''s ability to maintain fitness during infection (tolerance). Distinguishing between resistance and tolerance is important as they are thought to have markedly different evolutionary and epidemiological outcomes. Few studies have investigated tolerance in animals, and the extent of sexual dimorphism in tolerance is unknown. Using males and females from 50 Drosophila melanogaster genotypes, we investigated possible sources of genetic variation for immunity by assessing both resistance and tolerance to the common bacterial pathogen Pseudomonas aeruginosa. We found evidence of sexual dimorphism and sexual antagonism for resistance and tolerance, and a trade-off between the two traits. Our findings suggest that antagonistic pleiotropy may be a major contributor to variation in immunity, with implications for host–parasite coevolution.     

TOXOPLASMOSIS—The Protean Manifestations of the Condition and Their Significance in Pregnancy and in Newborn Infants

Toxoplasmosis is a relatively common and generally mild parasitic infection which can, however, produce fatal and crippling complications under certain conditions — particularly when a human fetus or a newborn infant is infected. In this instance, the infection is the result of a spread of the acquired disease which may occur in the mother in the last six months of pregnancy. Although the infection of adults can be dangerous and fatalities have been reported, the danger to the nervous system, eyes and other structures of the newborn infant can be devastating—blindness, brain damage and mental deficiency, particularly as the result of an obstruction to the flow of circulating cerebrospinal fluid within the brain.This report covers a number of differing features of the disease which have been described separately by other authors in specialty journals and in the foreign literature. If present, these signs should suggest toxoplasmosis, particularly in pregnancy, in the newborn infant and in still-born infants.Early diagnosis is of paramount interest in view of the poor response which may be obtained in the treatment of subacute and chronic phases of the illness. Difficulties in diagnosis stem from the manifestations of toxoplasmosis which closely resemble the symptoms of other infectious diseases.The clinical laboratory diagnosis is made by the isolation of the organism or by the demonstration of immune protein in the patient''s serum.     

THE ROLE OF THE CONNECTIVE TISSUE GROUND SUBSTANCES (MUCOPOLYSACCHARIDES) IN ALLERGIC INJURY

The basic histologic reactions of the classic allergic diseases and of several systemic diseases in which allergic mechanisms appear to operate are described and illustrated. Particular attention is drawn to the ground substances—mucopolysaccharides—which constitute important elements of connective tissue and vascular structure. The intimate locus of the allergic reaction appears to be in and to involve a swelling of such substances. It is suggested that antibodies (and possibly antigens) may be attached to these mucinous ground substances of the connective tissues.     

Immune Deficiency,Thrombocytopenia and Osteomyelitis in Pediatric Patients

Surgical decompression of osteomyelitis in pediatric patients should be an essential part of therapy in most cases. The initial deferral of prompt decompression in two patients because of underlying chronic, hemorrhagic (thrombocytopenic) disorders—one with Wiskott-Aldrich syndrome and one with Gaucher''s disease—resulted in more serious and prolonged courses of the infectious processes. The complications might have been ameliorated by earlier drainage in each case. Based upon the experience gained from these two patients, we recommend early drainage, with appropriate treatment of the hemorrhagic disorder, to prevent more widespread dissemination or prolongation of osseous infection in similarly affected children.     

Social network- and community-level influences on contraceptive use: evidence from rural Poland

The diffusion of ‘modern’ contraceptives—as a proxy for the spread of low-fertility norms—has long interested researchers wishing to understand global fertility decline. A fundamental question is how local cultural norms and other people''s behaviour influence the probability of contraceptive use, independent of women''s socioeconomic and life-history characteristics. However, few studies have combined data at individual, social network and community levels to simultaneously capture multiple levels of influence. Fewer still have tested if the same predictors matter for different contraceptive types. Here, we use new data from 22 high-fertility communities in Poland to compare predictors of the use of (i) any contraceptives—a proxy for the decision to control fertility—with those of (ii) ‘artificial’ contraceptives—a subset of more culturally taboo methods. We find that the contraceptive behaviour of friends and family is more influential than are women''s own characteristics and that community level characteristics additionally influence contraceptive use. Highly educated neighbours accelerate women''s contraceptive use overall, but not their artificial method use. Highly religious neighbours slow women''s artificial method use, but not their contraceptive use overall. Our results highlight different dimensions of sociocultural influence on contraceptive diffusion and suggest that these may be more influential than are individual characteristics. A comparative multilevel framework is needed to understand these dynamics.     

Genetic conflict,kin and the origins of novel genetic systems

Genetic conflict may have played an important role in the evolution of novel genetic systems. The ancestral system of eumendelian genetics is highly symmetrical. Those derived from it (e.g. thelytokous parthenogenesis, haplodiploidy and parent-specific allele expression) are more asymmetrical in the genetic role played by maternal versus paternal alleles. These asymmetries may have arisen from maternal–paternal genetic conflict, or cytonuclear conflict, or from an interaction between them. Asymmetric genetic systems are much more common in terrestrial and freshwater taxa than in marine taxa. We suggest three reasons for this, based on the relative inhospitability of terrestrial environments to three types of organism: (i) pathogens—departure from the marine realm meant escape from many pathogens and parasites, reducing the need for sexual reproduction; (ii) symbionts—symbionts are no more important in the terrestrial realm than the marine realm but are more likely to be obligately intracellular and vertically transmitted, making them more likely to disrupt their host''s genetic systems; (iii) Gametes and embryos—because neither gametes nor embryos can be shed into air as easily as into seawater, the mother''s body is a more important environment for both types of organisms in the terrestrial realm than in the marine realm. This environment of asymmetric kinship (with neighbours more closely related by maternal alleles than by paternal alleles) may have helped to drive asymmetries in expression and transmission.     

Ocular Complications in Renal Transplant Recipients

Twenty-five patients were examined for ocular complaints following renal transplantation. Besides the expected complications of posterior subcapsular cataract and cytomegalovirus retinitis, other findings—such as focal depigmentation of the retinal pigment epithelium, a lack of hypertensive retinopathy, elevated intraocular tensions, microaneurysms, preretinal wrinkling, serous detachments of the retina, hemorrhages and exudates—were observed.A laboratory clue to the onset of cytomegalovirus retinitis was a rapid rise in cytomegalovirus (CMV) antibody titer and a positive CMV plaque count in tissue culture.