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.
Describes how the "east-west" advancement flap with modifications can be used broadly for nasal defect surgery.
Mentorship has enhanced many careers, and it can be important in both job satisfaction and enjoyment; however, mentorships are complex human relationships and, as such, can be successful or can fail to be successful. This contribution explores some of the factors that facilitate both the success or failure of ethical mentorship relationships in medicine.
Case study: A 37-year-old white woman on over 10 years of immunosuppressive therapy for two successive renal transplants was seen in our dermatology clinic for a tender lesion on her left eyebrow which had grown rapidly over the previous few months.
Since its approval by the Food and Drug Administration (FDA) in 1982, isotretinoin has positively affected the lives of countless patients. Of course, any pharmaceutical agent has both its desired effect as well as undesirable side effects. The prescription of any given drug for any individual patient depends on the risk-benefit analysis for that patient. The side effect of teratogenicity has naturally moved to the forefront of safety standards for isotretinoin. It is important to remember that fetal exposure is the problem, not pregnancy itself, and all attention and efforts should be focused on preventing such exposure.
In the United States, 4 programs have been developed over time in an effort to prevent fetal exposure. These programs have been evaluated in terms of the numbers of pregnancies that occur, which is used as a proxy for potential fetal exposure. As we discuss the problem of teratogenicity with isotretinoin and the various programs to protect against it, we will use the term “pregnancies” as a representation of fetal exposure.
Prospective evaluation of dermatologic surgery complications including patients on multiple antiplatelet and anticoagulant medications
BACKGROUND: Few prospective studies have evaluated the safety of dermatologic surgery.
OBJECTIVE: We sought to determine rates of bleeding, infection, flap and graft necrosis, and dehiscence in outpatient dermatologic surgery, and to examine their relationship to type of repair, anatomic location of repair, antibiotic use, antiplatelet use, or anticoagulant use.
METHODS: Patients presenting to University of Massachusetts Medical School Dermatology Clinic for surgery during a 15-month period were prospectively entered. Medications, procedures, and complications were recorded.
RESULTS: Of the 1911 patients, 38% were on one anticoagulant or antiplatelet medication, and 8.0% were on two or more. Risk of hemorrhage was 0.89%. Complex repair (odds ratio [OR] = 5.80), graft repair (OR = 7.58), flap repair (OR = 11.93), and partial repair (OR = 43.13) were more likely to result in bleeding than intermediate repair. Patients on both clopidogrel and warfarin were 40 times more likely to have bleeding complications than all others (P = .03). Risk of infection was 1.3%, but was greater than 3% on the genitalia, scalp, back, and leg. Partial flap necrosis occurred in 1.7% of flaps, and partial graft necrosis occurred in 8.6% of grafts. Partial graft necrosis occurred in 20% of grafts on the scalp and 10% of grafts on the nose. All complications resolved without sequelae.
LIMITATIONS: The study was limited to one academic dermatology practice.
CONCLUSION: The rate of complications in dermatologic surgery is low, even when multiple oral anticoagulant and antiplatelet medications are continued, and prophylactic antibiotics are not used. Closure type and use of warfarin or clopidogrel increase bleeding risk. However, these medications should be continued to avoid adverse thrombotic events. All rights reserved.
Adverse effects of ultraviolet radiation from the use of indoor tanning equipment: time to ban the tan
The incidence of melanoma skin cancer is increasing rapidly, particularly among young women in the United States. Numerous studies have documented an association between the use of indoor tanning devices and an increased risk of skin cancer, especially in young women. Studies have shown that ultraviolet exposure, even in the absence of erythema or burn, results in DNA damage. Countries and regulatory bodies worldwide have recognized the health risks associated with indoor tanning. In the United States, 32 states have passed legislation to regulate the indoor tanning industry, but there is an urgent need to restrict the use of indoor tanning devices at the federal level. The Food and Drug Administration is currently reviewing the classification of these devices. For all of these reasons, the Food and Drug Administration should prohibit the use of tanning devices by minors and reclassify tanning devices to at least class II to protect the public from the preventable cancers and other adverse effects caused by ultraviolet radiation from indoor tanning. All rights reserved.
Dermatologic surgeons frequently encounter nasal tip defects after Mohs micrographic surgery. Correction of these defects presents a unique challenge. Slight flaws in design or technique may induce functional and aesthetic penalty. We present the columellar advancement flap, a novel repair option for nasal tip defects. When used appropriately, this technique results in concealed incision lines, preserved nasal symmetry, and optimal color and texture match. Additional advantages include reduction of “columellar sag” and increase of the nasolabial angle, resulting in more aesthetically pleasing nasal appearance.
A melanotic lentigo maligna (ALM) represents a small subset of lentigo maligna (LM) that lacks pigment. At least 2 cases of ALM responsive to imiquimod therapy with short-term follow-up have been reported. We report herein a case of ALM that failed to respond to imiquimod treatment. Furthermore, after therapy was initiated, the ALM began to produce pigment and transformed to LM.