Endoscopic Management of Gallbladder Disease.

PURPOSE OF REVIEW: Diseases of the gallbladder can be increasingly managed through endoscopic interventions, either serving as an alternative to or obviating the need for cholecystectomy. In this review, we aim to review the most recent data on endoscopic management of the most common gallbladder diseases. RECENT FINDINGS: The development of lumen-opposing metal stents (LAMS) marked a major shift in gallbladder management, with transmural techniques now well studied for management of cholecystitis. Endoscopic ultrasound (EUS) is also a well-developed technique for gallbladder imaging, comparable or superior to transabdominal ultrasound. Novel techniques with LAMS for gallbladder lesion/polyp resection and treatment of non-cholecystitis gallbladder diseases mark important milestones in gallbladder preservation and increasingly less invasive management of diseases of the gallbladder. There are multiple interventional endoscopic techniques that can be used to manage common gallbladder diseases including cholecystitis, cholelithiasis, gallbladder lesions/polyps, and gallbladder cancer. Ongoing development of novel therapeutic techniques holds promise for additional minimally invasive techniques in the future.

Dopaminylation in Psychostimulant Use Disorder Protects Against Psychostimulant Seeking Behavior by Normalizing Nucleus Accumbens (NAc) Dopamine Expression.

Background: Repeated cocaine administration changes histone acetylation and methylation on Lys residues and Deoxyribonucleic acid (DNA) within the nucleus accumbens (NAc). Recently Nestler's group explored histone Arg (R) methylation in reward processing models. Damez-Werno et al. (2016) reported that during human investigations and animal self-administration experiments, the histone mark protein-R-methyltransferase-6 (PRMT6) and asymmetric dimethylation of R2 on histone H3 (H3R2me2a) decreased in the rodent and cocaine-dependent human NAc. Overexpression of PRMT6 in D2-MSNs in all NAc neurons increased cocaine seeking, whereas PRMT6 overexpression in D1-MSNs protects against cocaine-seeking. Hypothesis: The hypothesis is that dopaminylation (H3R2me2a binding) occurs in psychostimulant use disorder (PSU), and the binding inhibitor Srcin1, like the major DRD2 A2 allelic polymorphism, protects against psychostimulant seeking behavior by normalizing nucleus accumbens (NAc) dopamine expression. Discussion: Numerous publications confirmed the association between the DRD2 Taq A1 allele (30-40 lower D2 receptor numbers) and severe cocaine dependence. Lepack et al. (2020) found that acute cocaine increases dopamine in NAc synapses, and results in histone H3 glutamine 5 dopaminylation (H3Q5dop) and consequent inhibition of D2 expression. The inhibition increases with chronic cocaine use and accompanies cocaine withdrawal. They also found that the Src kinase signaling inhibitor 1 (Srcin1 or p140CAP) during cocaine withdrawal reduced H3R2me2a binding. Consequently, this inhibited dopaminylation induced a "homeostatic brake." Conclusion: The decrease in Src signaling in NAc D2-MSNs, (like the DRD2 Taq A2 allele, a well-known genetic mechanism protective against SUD) normalizes the NAc dopamine expression and decreases cocaine reward and motivation to self-administer cocaine. The Srcin1 may be an important therapeutic target.

Colliding Bodies: Prostitutes, Soldiers, and Venereal Diseases in Colonial Egypt.

This article explores attempts to control outbreaks of venereal diseases among prostitutes and imperial soldiers in Cairo and Alexandria leading up to and through World War I. Seeking to move beyond the usual colonial framing of center-periphery, it considers two British imperial outposts-Egypt and Australia-in conversation. The war brought thousands of Australian soldiers to Egypt, leaving their mark on Egypt and becoming marked by their time there, sometimes in indelible and deadly ways, as bodies and bodily fluids collided, and microbes passed between colonial and imperial subjects. The article argues that the highly racialized and classed system for regulating foreign and local prostitution that British officials implemented in Egypt to protect soldiers exacerbated rather than contained the spread of venereal diseases.

Micro-geographic shift between negligible and actuarial senescence in a wild snake.

While it has long been known that species have contrasted life expectancy (pace of mortality) and generation time (pace of reproduction), recent studies have also uncovered that the shape of adult age trajectories of mortality and reproduction can vary remarkably among species along a continuum of senescence ranging from strong deterioration (senescence), insignificant deterioration (negligible senescence) to improvement with advancing age (negative senescence). As for many long-lived ectotherms with asymptotic growth and increasing reproductive output with age, snakes are good candidates for negligible senescence to occur. Yet, intraspecific variation in the pace and shape of actuarial and reproductive senescence across wild populations of these species remains to be explored. Here, we used 37 years of mark-recapture data in two nearby habitats inside a meadow viper Vipera ursinii population to quantify life expectancies, generation times and the shape of actuarial and reproductive senescence. Female vipers maintained stable reproductive performances at old ages, even when accounting for the predicted increase of fertility with body size, providing evidence for negligible reproductive senescence in both habitats. Males had a higher adult mortality and a shorter life expectancy on average than females and actuarial senescence shifted from negligible senescence in the optimal habitat to strong senescence in the sub-optimal habitat. Overall, these results demonstrate that micro-geographic environmental variation can generate qualitative shifts in actuarial senescence patterns. This highlights that taking into account the within-species plasticity of age-dependent trajectories could prove useful in better understanding what determines the evolution of life-history age trajectories.

La longévité et la manière de vieillir varient grandement entre espèces. Chez certaines espèces, la survie et la reproduction déclinent avec l'âge : les individus souffrent de sénescence. Chez d'autres, les vieux individus maintiennent des performances reproductives et de survie similaires à celles des jeunes : la sénescence est alors dite négligeable. Enfin, la sénescence peut être négative quand la survie des adultes ou leur reproduction s'améliorent avec l'âge. Les formes des trajectoires de mortalité et de reproduction avec l'âge sont encore mal connues chez les serpents, mais la théorie évolutive prédit une sénescence négligeable chez les espèces qui, comme les serpents, continuent à grandir à l'âge adulte et dont les femelles produisent des portées dont l'effectif augmente avec la taille corporelle de la mère. Nous avons exploité ici 37 années de données de capture-marquage-recapture de vipères d'Orsini, Vipera ursinii ursinii, dans deux habitats voisins d'une petite population isolée du Sud-Est de la France pour quantifier l'espérance de vie, les temps de génération et les formes de la sénescence de survie et de la sénescence reproductrice. Nous montrons que les vipères femelles parviennent à maintenir de bonnes performances reproductives même à des âges avancés, illustrant une sénescence reproductrice négligeable dans cette population. Nous montrons aussi que la forme de la sénescence de survie varie fortement à une très petite échelle géographique : dans l'habitat optimal, la survie adulte des vipères demeure stable quel que soit leur âge alors qu'à quelques centaines de mètres, dans un habitat moins favorable, les vipères subissent une forte sénescence de survie. Ces résultats démontrent que de forts changements qualitatifs dans les profils de sénescence peuvent être observés à une échelle spatiale réduite. Cette plasticité intra-spécifique de la sénescence offre de nouvelles perspectives pour mieux comprendre ce qui détermine l'évolution de la sénescence.

Transethnic meta-analysis identifies GSDMA and PRDM1 as susceptibility genes to systemic sclerosis.

OBJECTIVES: Systemic sclerosis (SSc) is an autoimmune disease characterised by skin and systemic fibrosis culminating in organ damage. Previous genetic studies including genome-wide association studies (GWAS) have identified 12 susceptibility loci satisfying genome-wide significance. Transethnic meta-analyses have successfully expanded the list of susceptibility genes and deepened biological insights for other autoimmune diseases. METHODS: We performed transethnic meta-analysis of GWAS in the Japanese and European populations, followed by a two-staged replication study comprising a total of 4436 cases and 14 751 controls. Associations between significant single nuclear polymorphisms (SNPs) and neighbouring genes were evaluated. Enrichment analysis of H3K4Me3, a representative histone mark for active promoter was conducted with an expanded list of SSc susceptibility genes. RESULTS: We identified two significant SNP in two loci, GSDMA and PRDM1, both of which are related to immune functions and associated with other autoimmune diseases (p=1.4×10-10 and 6.6×10-10, respectively). GSDMA also showed a significant association with limited cutaneous SSc. We also replicated the associations of previously reported loci including a non-GWAS locus, TNFAIP3. PRDM1 encodes BLIMP1, a transcription factor regulating T-cell proliferation and plasma cell differentiation. The top SNP in GSDMA was a missense variant and correlated with gene expression of neighbouring genes, and this could explain the association in this locus. We found different human leukocyte antigen (HLA) association patterns between the two populations. Enrichment analysis suggested the importance of CD4-naïve primary T cell. CONCLUSIONS: GSDMA and PRDM1 are associated with SSc. These findings provide enhanced insight into the genetic and biological basis of SSc.

In vitro long-term treatment with MAPK inhibitors induces melanoma cells with resistance plasticity to inhibitors while retaining sensitivity to CD8 T cells.

The development of BRAF V600 and MEK inhibitors constitutes a breakthrough in the treatment of patients with BRAF-mutated metastatic melanoma. However, although there is an increase in overall survival, these patients generally confront recurrence, and several resistance mechanisms have already been described. In the present study we describe a different resistance mechanism. After several weeks of long­term in vitro treatment of two different V600E BRAF­mutated melanoma cell lines with MARK inhibitors, PLX4032 and/or GDC-0973, the majority of the cells died whereas some remained viable and quiescent (SUR). Markedly, discontinuing treatment of SUR cells with MAPK inhibitors allowed the population to regrow and these cells retained drug sensitivity equal to that of the parental cells. SUR cells had increased expression levels of CD271 and ABCB5 and presented senescence-associated characteristics. Notably, SUR cells were efficiently lysed by cytotoxic T lymphocytes recognizing MART-1 and gp100 melanoma differentiation antigens. We propose quiescent plasticity as a mechanism of resistance to BRAF and MEK inhibitors while retaining sensitivity to immune effectors.

Peste des petits ruminants: a suitable candidate for eradication?

This year will see the final announcement, accompanied by much justifiable celebration, of the eradication from the wild of rinderpest, the 'cattle plague' that has been with us for so many centuries. The only known rinderpest virus (RPV) remaining is in a relatively small number of laboratories around the world, and in the stockpiles of vaccine held on a precautionary basis. As we mark this achievement, only the second virus ever eradicated through human intervention, it seems a good time to look at rinderpest's less famous cousin, peste des petits ruminants ('the plague of small ruminants') and assess if it should, and could, also be targeted for global eradication.

Cohort variation in offspring growth and survival: prenatal and postnatal factors in a late-maturing viviparous snake.

1. Recruitment to adulthood plays an important role in the population dynamics of late-maturing organisms as it is usually variable. Compared to birds and mammals, few studies assessing the contributions to this variation of environmental factors, offspring traits and maternal traits have been carried out for late-maturing snakes. 2. Cohort variation in recruitment through offspring growth and survival in the meadow viper (Vipera ursinii ursinii) was evaluated from 13 years of mark-recapture data collected at Mont Ventoux, France. In this species, females are mature at the age of 4-6 years and adult survival and fecundity rates are high and constant over time. 3. Offspring were difficult to catch during the first 3 years of their lives, but their mean annual probability of survival was reasonably high (0.48 +/- 0.11 SE). Mass and body condition at birth (mass residuals) varied significantly between years, decreased with litter size, and increased with maternal length. 4. Cohorts of offspring in better condition at birth grew faster, but offspring growth was not affected by sex, habitat or maternal traits. 5. Survival varied considerably between birth cohorts, some cohorts having a high-survival rate and others having essentially no survivors. No difference in mass or body condition at birth was found between cohorts with 'no survival' and 'good survival'. However, offspring survival in cohorts with good survival was positively correlated with mass at birth and negatively correlated with body condition at birth. 6. Thus, variation in offspring performance was influenced by direct environmental effects on survival and indirect environmental effects on growth, mediated by body condition at birth. Effects of maternal traits were entirely channelled through offspring traits.

Voxel-based mapping of brain gray matter volume and glucose metabolism profiles in normal aging.

With age, the brain undergoes both structural and functional alterations, probably resulting in reported cognitive declines. Relatively few investigations have sought to identify those areas that remain intact with aging, or undergo the least deterioration, which might underlie cognitive preservations. Our aim here was to establish a comprehensive profile of both structural and functional changes in the aging brain, using up-to-date voxel-based methodology (i.e. optimized voxel-based morphometry (VBM) procedure; resting-state (18)FDG-PET with correction for partial volume effects (PVE)) in 45 optimally healthy subjects aged 20-83 years. Negative and positive correlations between age and both gray matter (GM) volume and (18)FDG uptake were assessed. The frontal cortex manifested the greatest deterioration, both structurally and functionally, whereas the anterior hippocampus, the thalamus and (functionally) the posterior cingulate cortex were the least affected. Our results support the developmental theory which postulates that the first regions to emerge phylogenetically and ontogenetically are the most resistant to age effects, and the last ones the most vulnerable. Furthermore, the lesser affected anterior hippocampal region, together with the lesser functional alteration of the posterior cingulate cortex, appear to mark the parting of the ways between normal aging and Alzheimer's disease, which is characterized by early and prominent deterioration of both structures.

Constitutive cytokine mRNAs mark natural killer (NK) and NK T cells poised for rapid effector function.

Natural killer (NK) and NK T cells are tissue lymphocytes that secrete cytokines rapidly upon stimulation. Here, we show that these cells maintain distinct patterns of constitutive cytokine mRNAs. Unlike conventional T cells, NK T cells activate interleukin (IL)-4 and interferon (IFN)-gamma transcription during thymic development and populate the periphery with both cytokine loci previously modified by histone acetylation. Similarly, NK cells transcribe and modify the IFN-gamma gene, but not IL-4, during developmental maturation in the bone marrow. Lineage-specific patterns of cytokine transcripts predate infection and suggest evolutionary selection for invariant but distinct types of effector responses among the earliest responding lymphocytes.

Multiple ex vivo organ preservation with warm whole blood.

To determine the feasibility of en bloc removal of the heart, lungs, liver, kidneys, and pancreas for preservation with warm blood autoperfusion, organs from 34 dogs were preserved ex vivo for periods of between 3 and 22 hours. The lungs were ventilated with a Bird Mark 7 respirator, and the heart served as the pump to perfuse all organs of the multiple organ block. In the first group of 28 animals, surgical and pharmacologic techniques were developed to permit management of the ex vivo model. The last six experiments were conducted in a standardized fashion for a period of 6 hours and evaluated on the basis of hemodynamic, biochemical, and pathologic measurements. In this group the pH level remained stable and blood gas levels remained within normal limits for inspired oxygen of 0.2. Serum and urine electrolyte levels were easily maintained within normal limits. Serum enzyme values were elevated initially after operation, and this increase persisted throughout the preservation period in most animals. Continuing refinements in surgical technique, pharmacologic management, and chamber development resulted in a dramatic reduction of the edema and organ damage seen on pathologic studies of the initial experiments. The presence of focal lymphatic congestion, however, was noted even in the animals in group II and may have been related to ligation of major lymphatic channels or to endothelial loss. These changes could contribute to the development of the pathologic changes seen in irreversible shock. Preservation of the multiple organ block by warm autoperfusion is an important step in understanding the physiology of organ preservation and has potential for permitting prolonged organ preservation. Studies are continuing to further analyze this model and prolong the time of preservation. Final assessment of the model will be transplantation of the preserved organs and evaluation of function after implantation.

Activated T-cells and macrophages in the cerebrospinal fluid and the spinal meningeal exudate in chronic relapsing experimental allergic encephalomyelitis.

An analysis has been made of the cell types which mark with monoclonal antibodies against T cells, macrophages and the IL-2 receptor (anti-Tac) in the blood, cerebrospinal fluid (CSF) and spinal meningeal exudates taken from guinea pigs in the relapse and remission stages of chronic relapsing experimental allergic encephalomyelitis (CR-EAE). Whilst the T-cell and macrophage content of blood remained unchanged throughout the course of CR-EAE, T cells accounted for the majority of the CSF pleocytosis associated with relapsing disease but both T cells and macrophages populated the meningeal exudate in substantial numbers. Activated T cells (Tac+) rose in number in blood only after the onset of relapse but formed a far higher proportion of the CSF pleocytosis or meningeal exudate than in paired blood samples. Meningeal exudate cells from Freund's adjuvant-inoculated, but not uninoculated animals, also showed an increase in Tac+ cell levels. In addition, the meningeal exudate contained a substantial number of cells which did not label with anti-T or anti-macrophage antibodies and which did not vary in absolute numbers throughout the course of disease.

Effect of spaceflight on the non-weight-bearing bones of rat skeleton.

Male Wistar rats prelabeled with tetracycline to mark surfaces of bone and tooth formation-mineralization were placed into orbit for 18.5 days aboard the Soviet COSMOS-1129 Biosatellite. They were injected with tetracycline for a second and third time on the 6th and 27th days, respectively, after recovery of the Biosatellite. Spaceflight did not alter the rate of periosteal bone formation in the non-weight-bearing ribs and regions of the mandibles, which were covered by masticatory muscles. Bone formation-calcification rates were impaired at those sites in the jaw that had no contiguous muscle (molar region). The remodeling activity on the alveolar bone around the buccal roots of the molar teeth was significantly reduced but without creating a negative balance between formative and resorptive activities. Total Ca, P, and hydroxyproline concentrations in the jaws, incisors, and ribs were normal after spaceflight, but gravity density fractionation studies indicated that in the jaws alone, O-G conditions caused a delay in the maturation of bone mineral and matrix. A 29-day postflight recovery period at earth's gravity was sufficient to fully correct these anomalies. Relative to tooth formation, relatively normal circadian and infradian biorhythmic periodicities of Ca and P in dentin and enamel were maintained during spaceflight. We conclude that most of the non-weight-bearing bones of the rat skeleton are at risk to the effects of hypogravity.