Bloom Syndrome (BS, MIM #210900) is an autosomal recessive genetic disorder caused by a mutation in the BLM gene, which codes for the DNA repair enzyme RecQL3 helicase. Without proper DNA repair mechanisms, abnormal DNA exchange takes place between sister chromatids and results in genetic instability that may lead to cancer, especially lymphoma and acute myelogenous leukemia, lower and upper gastrointestinal tract neoplasias, cutaneous tumors, and neoplasias in the genitalia and urinary tract. BS patients are usually of Ashkenazi Jewish descent and exhibit narrow facial features, elongated limbs, and several dermatologic complications including photosensitivity, poikiloderma, and telangiectatic erythema. The most concerning manifestation of BS is multiple malignancies, which require frequent screenings and strict vigilance by the physician. Therefore, distinguishing between BS and other dermatologic syndromes of similar presentation such as Rothmund-Thomson Syndrome, Erythropoietic Protoporphyria, and Cockayne Syndrome is paramount to disease management and to prolonging life. BS can be diagnosed through a variety of DNA sequencing methods, and genetic testing is available for high-risk populations. This review consolidates several sources on BS sequelae and aims to suggest the importance of differentiating BS from other dermatologic conditions. This paper also elucidates the recently discovered BRAFT and FANCM protein complexes that link BS and Fanconi anemia.
Screening of small-molecule libraries is an important aspect of probe and drug discovery science. Numerous authors have suggested that bioactive natural products are attractive starting points for such libraries because of their structural complexity and sp(3)-rich character. Here, we describe the construction of a screening library based on representative members of four families of biologically active alkaloids (Stemonaceae, the structurally related cyclindricine and lepadiformine families, lupin and Amaryllidaceae). In each case, scaffolds were based on structures of the naturally occurring compounds or a close derivative. Scaffold preparation was pursued following the development of appropriate enabling chemical methods. Diversification provided 686 new compounds suitable for screening. The libraries thus prepared had structural characteristics, including sp(3) content, comparable to a basis set of representative natural products and were highly rule-of-five compliant.
Drug rash with eosinophilia and systemic symptoms syndrome is a severe idiosyncratic drug reaction with a long latency period. It has been described using many terms; however, drug rash with eosinophilia and systemic symptoms syndrome appears to be the most appropriate. This syndrome causes a diverse array of clinical symptoms, anywhere from 2 to 8 weeks after initiating the offending drug. Standardized criteria for the diagnosis have been developed; however, their utility remains to be validated. Unfortunately, the management of drug rash with eosinophilia and systemic symptoms syndrome is not well supported by strong evidence-based data.
Mitral valve prolapse is the most common disorder of the cardiac valves in people in the United States. It can present as both primary and secondary disorders, and when associated with myxomatous changes in the skin, the term cardiocutaneous mucinosis can be used to describe this entity. Patients with mitral valve prolapse may have cutaneous findings on histological analysis that may indicate its severity and complication rate.
Multiple cutaneous and uterine leiomyomatosis is an autosomal dominant disease characterized by leiomyomas of the skin and uterus. A small proportion of patients affected by multiple cutaneous and uterine leiomyomatosis will develop renal cell carcinoma and this condition is known as hereditary leiomyomatosis and renal cell carcinoma. Diagnosis usually occurs during histological analysis of a cutaneous biopsy. Management should involve a multidisciplinary team along with periodical radiological studies to closely monitor tumor size in the uterus and kidneys. Gonadotropin-releasing hormone analogues are helpful in reducing the size of uterine fibroids.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephelopathy is an autosomal dominant disease affecting small vessels and often resulting in subcortical infarcts. A skin biopsy may facilitate its diagnosis as the cutaneous surface is much easier to sample than the central nervous systems tissue. Unfortunately, there is no effective treatment available today.
The discovery of the Merkel cell polyomavirus (MCV) in a large number of Merkel cell carcinomas (MCCs) has led to many investigations into its potential role as an oncovirus. Many studies have recently explored the differences between MCCs infected and not infected with MCV.
To determine whether the relative proportions of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive S aureus (MSSA) were changing or stable in an outpatient dermatology clinic and to examine the antibiotic susceptibility profiles of S aureus isolates.
The full details of our enantioselective formal synthesis of the biologically active natural product berkelic acid are described. The insertion of the C-18 methyl group proved challenging, with three different approaches investigated to install the correct stereochemistry. Our initial Horner-Wadsworth-Emmons/oxa-Michael approach to the berkelic acid core proved unsuccessful upon translation to the natural product itself. However, addition of a silyl enol ether to an oxonium ion, followed by a one-pot debenzylation/spiroketalisation/thermodynamic equilibration procedure, afforded the tetracyclic structure of the berkelic acid core as a single diastereoisomer.
An enantioselective formal synthesis of berkelic acid is described. The key step involves a late-stage silyl enol ether addition to a benzannulated oxonium ion with subsequent spiroketalization leading to construction of the tetracyclic core. Thermodynamically controlled equilibration under acidic conditions affords the desired spiroketal configuration as a single diastereoisomer.
Scars are usually classified into atrophic scars, hypertrophic scars, or keloids. A number of lasers, both with known and unknown mechanisms of action, have been investigated for improving the appearance of such scars, with variable outcomes. Currently, multiple lasers are being utilized for the treatment of scars. The 585 nm pulsed dye laser is the gold standard of laser therapy for keloid and hypertrophic scars. The ablative lasers such as the CO(2) and Er:YAG lasers are best suited for atrophic scars. Non-ablative approaches have also become popular and are being widely used to achieve reduced downtimes yet still provide excellent outcomes. This chapter discusses these lasers and their role in scar improvement.
Basal cell carcinomas (BCC) have a specialized microvasculature system that can be targeted by the 585-nm pulsed dye laser (PDL) utilizing the theory of selective photothermolysis. Seven volunteers with nine well-defined, biopsy-proven BCCs, were treated with the PDL (585-nm wavelength, a single 450-?s pulse, 7-mm spot size, and 9.0 J/cm(2) energy). The lesions, along with a 4-mm border of normal skin were treated. Pain assessment was carried out immediately after the laser treatment. A deep shave biopsy with histological examination occurred 4 weeks after the laser treatment. Pain was assessed on a scale of 0 (no pain) to 10 (worst pain possible). The average patient score was 2.1 (range 1-4). On histology, 5/9 (55.6%) sites demonstrated no evidence of BCC; however, 4/9 (44.4%) sites showed residual BCC. Although the PDL was able to clear over half of the BCCs in this study, there was an unacceptably high persistence rate of 44.4%. The PDL did not achieve the clearance rate that can be attained with current standard BCC treatment modalities. At this time, we do not recommend that a single treatment with the 585-nm PDL can be used as a primary therapy for BCC.
The phenylacetyl-CoA (Paa) catabolic pathway and genome-wide gene expression responses to phenylacetate catabolism were studied in the polychlorinated biphenyl (PCB)-degrading strain Burkholderia xenovorans LB400. Microarray and RT-qPCR analyses identified three non-contiguous chromosomal clusters of genes that are predicted to encode a complete Paa pathway that were induced up to 40-fold during growth of LB400 on phenylacetate: paaGHIJKR, paaANEBDF, and paaC. Comparison of the available genome sequences revealed that this organization is unique to Burkholderiaceae. Parallel proteomic studies identified 7 of the 14 predicted Paa proteins, most of which were detected only in phenylacetate-grown cells, but not in benzoate- or succinate-grown cells. Finally, the transcriptomic and proteomic analyses revealed the induction of at least 7 predicted catabolic pathways of aromatic compounds and some aromatic plant products (phenols, mandelate, biphenyl, C(1) compounds, mevalonate, opine, and isoquinoline), as well as an oxidative stress response and a large group of transporters. Most of these genes were not induced during growth on benzoate or biphenyl, suggesting that phenylacetate or a metabolite may act as a signal that triggers multiple physiological processes. Identifying the components of the Paa pathway is important since the pathway appears to contribute to virulence of Burkholderia pathogens.
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is a rare autoimmune disorder. The clinical spectrum of symptoms is diverse; the diagnosis relying on the presence of at least two out of the three main conditions defining the syndrome: chronic mucocutaneous candidiasis, hypoparathyroidism, and Addisons disease.
Warts are the most common nail tumor generally caused by human papilloma virus (HPV) 1, 2, 4, 27, and 57. HPV 16 and 18 are associated with malignant transformation to squamous cell carcinoma, while HPV 2 and 7 are associated with "butchers warts." Current treatments range from topical and intralesional therapies to systemic agents and surgical procedures. Despite the numerous available possibilities for treatment, intralesional bleomycin appears to be the most effective treatment for periungual warts.
Adenopathy and extensive skin patch overlying a plasmacytoma is a very rare syndrome featuring a red-to-brown, violaceous skin patch along with a plasmacytoma. Only 11 case reports exist in the literature. Skin biopsies from the cutaneous patch overlying the plasmacytoma exhibit a dermal vascular hyperplasia with increased surrounding dermal mucin. Radiation therapy is used to treat and cure the plasmacytoma.
In 2007, the International Knockout Mouse Consortium (IKMC) made the ambitious promise to generate mutations in virtually every protein-coding gene of the mouse genome in a concerted worldwide action. Now, 5 years later, the IKMC members have developed high-throughput gene trapping and, in particular, gene-targeting pipelines and generated more than 17,400 mutant murine embryonic stem (ES) cell clones and more than 1,700 mutant mouse strains, most of them conditional. A common IKMC web portal (www.knockoutmouse.org) has been established, allowing easy access to this unparalleled biological resource. The IKMC materials considerably enhance functional gene annotation of the mammalian genome and will have a major impact on future biomedical research.
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