In female mice, two forms of X-chromosome inactivation (XCI) ensure the selective silencing of female sex chromosomes during mouse embryogenesis. Beginning at the four-cell stage, imprinted XCI (iXCI) exclusively silences the paternal X chromosome. Later, around implantation, epiblast cells of the inner cell mass that give rise to the embryo reactivate the paternal X chromosome and undergo a random form of XCI (rXCI). Xist, a long non-coding RNA crucial for both forms of XCI, is activated by the ubiquitin ligase RLIM (also known as Rnf12). Although RLIM is required for triggering iXCI in mice, its importance for rXCI has been controversial. Here we show that RLIM levels are downregulated in embryonic cells undergoing rXCI. Using mouse genetics we demonstrate that female cells lacking RLIM from pre-implantation stages onwards show hallmarks of XCI, including Xist clouds and H3K27me3 foci, and have full embryogenic potential. These results provide evidence that RLIM is dispensable for rXCI, indicating that in mice an RLIM-independent mechanism activates Xist in the embryo proper.
Estrogen defines the dorsal-ventral limit of VEGF regulation to specify the location of the hemogenic endothelial niche
Genetic control of hematopoietic stem and progenitor cell (HSPC) function is increasingly understood; however, less is known about the interactions specifying the embryonic hematopoietic niche. Here, we report that 17beta-estradiol (E2) influences production of runx1+ HSPCs in the AGM region by antagonizing VEGF signaling and subsequent assignment of hemogenic endothelial (HE) identity. Exposure to exogenous E2 during vascular niche development significantly disrupted flk1+ vessel maturation, ephrinB2+ arterial identity, and specification of scl+ HE by decreasing expression of VEGFAa and downstream arterial Notch-pathway components; heat shock induction of VEGFAa/Notch rescued E2-mediated hematovascular defects. Conversely, repression of endogenous E2 activity increased somitic VEGF expression and vascular target regulation, shifting assignment of arterial/venous fate and HE localization; blocking E2 signaling allowed venous production of scl+/runx1+ cells, independent of arterial identity acquisition. Together, these data suggest that yolk-derived E2 sets the ventral boundary of hemogenic vascular niche specification by antagonizing the dorsal-ventral regulatory limits of VEGF.
Book chapter describing complications and emergencies that might arise during dermatological surgery.
Publisher description: Surgical dermatology is a growing field reflecting the increasing incidence of photodamage and sun-related tumors, whether benign or malignant. These diseases require expert pathological diagnosis -- sometimes interoperatively -- and therefore all it is important to learn not only techniques of lesion removal, but also specimen preparation and histological appearance. Surgical dermatology covers the gamut of surgical skin lesions, clinical features, histologic subtypes, frozen section and permanent section interpretation, and differential diagnosis. Normal variants are covered in depth. Laboratory techniques for frozen, permanent and MOHS fixed tissue preparation are given. There is a very useful section on artifacts and margin control, both of which have important practical implications. Because other dermatopathology texts cover all dermatologic diseases, they do not focus in such depth on the particular problems of technique and recognition proposed by dermatosurgical specimens.
Publisher description: This book was written to fill a perceived void in the current literature. Cutaneous Oncology is designed to focus on the nature and behaviour of cancers, standing at the junction of clinical medicine and basic science research to provide a whole picture of skin tumor biology to both clinicians and researchers. The book explains our clinical understanding of skin cancers in terms of their biological and molecular bases, and provides a framework of clinical settings in which to understand and appreciate the importance of individual facets of tumor biology.
Publisher description: This volume is a comprehensive and highly practical textbook of dermatologic surgery. The book provides clear, detailed, step-by-step how-to instructions for all available surgical procedures and techniques and offers precise guidance on recognizing pitfalls, avoiding complications, and managing them when they occur. Close attention is also given to postoperative management. More than 1,200 detail-revealing illustrations complement the text throughout. Coverage encompasses all procedures using steel instruments and lasers and special procedures such as Mohs surgery, cryosurgery, electrosurgery, dermabrasion, chemical peels, hair replacement, suction lipectomy, augmentation, and sclerotherapy. For each procedure, the text discusses preoperative planning; technique, with anatomic considerations if applicable; postoperative management; and complications.
Differential Muscle Hypertrophy Is Associated with Satellite Cell Numbers and Akt Pathway Activation Following Activin Type IIB Receptor Inhibition in Mtm1 p.R69C Mice
X-linked myotubular myopathy is a congenital myopathy caused by deficiency of myotubularin. Patients often present with severe perinatal weakness, requiring mechanical ventilation to prevent death from respiratory failure. We recently reported that an activin receptor type IIB inhibitor produced hypertrophy of type 2b myofibers and modest increases of strength and life span in the severely myopathic Mtm1δ4 mouse model of X-linked myotubular myopathy. We have now performed a similar study in the less severely symptomatic Mtm1 p.R69C mouse in hopes of finding greater treatment efficacy. Activin receptor type IIB inhibitor treatment of Mtm1 p.R69C animals produced behavioral and histological evidence of hypertrophy in gastrocnemius muscles but not in quadriceps or triceps. The ability of the muscles to respond to activin receptor type IIB inhibitor treatment correlated with treatment-induced increases in satellite cell number and several muscle-specific abnormalities of hypertrophic signaling. Treatment-responsive Mtm1 p.R69C gastrocnemius muscles displayed lower levels of phosphorylated ribosomal protein S6 and higher levels of phosphorylated eukaryotic elongation factor 2 kinase than were observed in Mtm1 p.R69C quadriceps muscle or in muscles from wild-type littermates. Hypertrophy in the Mtm1 p.R69C gastrocnemius muscle was associated with increased levels of phosphorylated ribosomal protein S6. Our findings indicate that muscle-, fiber type-, and mutation-specific factors affect the response to hypertrophic therapies that will be important to assess in future therapeutic trials.
A number of pathogens cause host cell death upon infection, and Yersinia pestis, infamous for its role in large pandemics such as the "Black Death" in medieval Europe, induces considerable cytotoxicity. The rapid killing of macrophages induced by Y. pestis, dependent upon type III secretion system effector Yersinia outer protein J (YopJ), is minimally affected by the absence of caspase-1, caspase-11, Fas ligand, and TNF. Caspase-8 is known to mediate apoptotic death in response to infection with several viruses and to regulate programmed necrosis (necroptosis), but its role in bacterially induced cell death is poorly understood. Here we provide genetic evidence for a receptor-interacting protein (RIP) kinase-caspase-8-dependent macrophage apoptotic death pathway after infection with Y. pestis, influenced by Toll-like receptor 4-TIR-domain-containing adapter-inducing interferon-β (TLR4-TRIF). Interestingly, macrophages lacking either RIP1, or caspase-8 and RIP3, also had reduced infection-induced production of IL-1β, IL-18, TNF, and IL-6; impaired activation of the transcription factor NF-κB; and greatly compromised caspase-1 processing. Cleavage of the proform of caspase-1 is associated with triggering inflammasome activity, which leads to the maturation of IL-1β and IL-18, cytokines important to host responses against Y. pestis and many other infectious agents. Our results identify a RIP1-caspase-8/RIP3-dependent caspase-1 activation pathway after Y. pestis challenge. Mice defective in caspase-8 and RIP3 were also highly susceptible to infection and displayed reduced proinflammatory cytokines and myeloid cell death. We propose that caspase-8 and the RIP kinases are key regulators of macrophage cell death, NF-κB and inflammasome activation, and host resistance after Y. pestis infection.
The purpose of this article is to describe my experience during the last few days of my father's life. My father had been suffering with dementia for approximately eight years. As a family, we worked together to plan his care. However, we were not prepared for his last days of life. Understanding the process helped me cope with the end of my father's life. The end of the article includes links to some freely available resources to help you, your family, and your patrons.
Cognitive Status and Initiation of Lifestyle Changes Following Acute Coronary Heart Syndrome: A Dissertation
Background: Cognitive impairment is prevalent in survivors of acute coronary syndrome (ACS) and increases risk for poor outcomes. Lifestyle changes are recommended to patients after ACS to reduce their risk for recurrent events, but cognitively impaired patients may encounter difficulties initiating these changes. This dissertation had three aims: (1) to examine cognitive status as a predictor of lifestyle changes after ACS, (2) to examine whether caregiver support moderates the association of cognitive status and initiation of lifestyle changes, and (3) to assess the reliability of self-reported lifestyle changes in cognitively impaired patients through comparison of their reports of lifestyle change with those from their caregivers.
Methods: For aims 1 and 2, Poisson regression with robust error variance was used to examine the association of cognitive status and caregiver support with patient-reported initiation of five lifestyle changes (improving diet, increasing exercise, quitting smoking, reducing stress, and attending cardiac rehabilitation) in 881 patients from TRACE-CORE, a prospective longitudinal observational study of outcomes in ACS. For aim 3, pilot data from 78 patient-caregiver dyads from TRACE-CARE, an ancillary substudy, were used to examine whether patient-caregiver congruence on reports of lifestyle changes varied according to patients’ cognitive function.
Results: Patient-reported rates of lifestyle change did not vary according to cognitive status, except for participation in cardiac rehabilitation. Caregiver support improved patient-reported rates of lifestyle change among cognitively intact patients but not cognitively impaired patients. Patients’ cognitive function was positively associated with patient-caregiver congruence on reports of initiation of lifestyle changes and patients with decreased cognitive function tended to over-report initiation of lifestyle changes compared to reports by their caregivers.
Conclusion: Although cognitive status was not associated with initiation of most lifestyle changes and the influence of caregiver support on initiation of lifestyle changes was only beneficial to cognitively intact patients in this cohort of ACS patients, these null findings may be explained by the questionable validity of self-report in cognitively impaired patients. This dissertation yields new knowledge about secondary prevention in ACS patients and provides insight into the challenges of conducting patient-reported outcomes research in cognitively compromised populations.
An update on the basic science and clinical aspects of basosquamous carcinoma.
This review identifies frozen section artifacts created during Mohs surgical techniques, marking and orientation of tissue, tissue mounting and processing, slide preparation, and deposition (foreign body) artifacts. It discusses ways to prevent such changes and illustrates examples of artifacts in frozen section preparation.
This manual offers information for establishing a practice in dermatologic surgery, providing guidelines for equipping the dermatology office for surgical and anaesthestic procedures. The author aims to help with the decisions involved in office design, instrumentation and equipment purchases.
Summary: Artifacts in Mohs sections can be the result of surgical technique, mounting, processing, or staining. Artifacts, especially cautery and freeze artifacts, can mimic tumor. Understanding the cause of artifacts can be important in preventing or correctly interpreting them.
This chapter will cover a wide variety of complications in cutaneous surgery without a common uniting theme. Some topics are well established in the literature, whereas others are well recognized, common problems that have not been researched extensively. References may be sparse or nonexistent in some areas. These miscellaneous complications are still important and the cutaneous surgeon should be capable of avoiding them before they occur and treating them once they arise.
Dermatologic surgery is changed in the pregnant and postpartum patient. The physiologic changes associated with pregnancy require attention to the timing of surgery as well as the positioning and technique to maximize the outcome for the patient. The surgeon must also remember the risks to the fetus or nursing newborn in planning any surgical procedure. This is the one time when there is more than one patient in every procedure. This article will review the timing of surgery, tumors of pregnancy, surgical positioning, local anesthetics, surgical technique, and cosmetic procedures. This information should help provide a safe surgical procedure for the mother and the child.
From Introduction: In 2005, the American Academy of Dermatology established an Academic Dermatology Leadership Program (ADLP). This program has been well received, with consistently positive formal and informal evaluations. Moreover, participants report very high retention rates in full-time academic practice (>75%). An important component of the ADLP is the matching of participants, who are early in their career as academic dermatologists, with a mentor—often located at a distant geographic locations—as a way to help them succeed in the field and advance as leaders. In most cases, mentorship is conducted primarily via phone calls with only a few in-person meetings. While this approach can pose unique challenges, it has great potential, particularly in a field like dermatology. Most academic departments in dermatology are small, and the opportunity to be matched with a mentor from a different institution with a different perspective can be especially valuable. This article aims to outline strategies shared from informal discussions among the authors, all of whom have participated in the ADLP, to optimize such “long-distance”, extramural mentoring relationships, and to describe some of the lessons learned from these relationships. It is not meant to be a comprehensive review of mentoring or mentoring strategies, but rather to provide ideas for “jump-starting” this unique type of relationship. Many of the principles described herein may be applied not only to academic dermatologists, but also to those in community-based practices, at other career stages, as well as in other disciplines.