Three inherited autosomal dominant conditions-BRCA-related hereditary breast and ovarian cancer (HBOC), Lynch syndrome (LS) and familial hypercholesterolemia (FH)-have been termed the Centers for ...Disease Control and Prevention Tier 1 (CDCT1) genetic conditions, for which early identification and intervention have a meaningful potential for clinical actionability and a positive impact on public health
. In typical medical practice, genetic testing for these conditions is based on personal or family history, ethnic background or other demographic characteristics
. In this study of a cohort of 26,906 participants in the Healthy Nevada Project (HNP), we first evaluated whether population screening could efficiently identify carriers of these genetic conditions and, second, we evaluated the impact of genetic risk on health outcomes for these participants. We found a 1.33% combined carrier rate for pathogenic and likely pathogenic (P/LP) genetic variants for HBOC, LS and FH. Of these carriers, 21.9% of participants had clinically relevant disease, among whom 70% had been diagnosed with relevant disease before age 65. Moreover, 90% of the risk carriers had not been previously identified, and less than 19.8% of these had documentation in their medical records of inherited genetic disease risk, including family history. In a direct follow-up survey with all carriers, only 25.2% of individuals reported a family history of relevant disease. Our experience with the HNP suggests that genetic screening in patients could identify at-risk carriers, who would not be otherwise identified in routine care.
Glycoproteins traversing the eukaryotic secretory pathway begin life in the endoplasmic reticulum (ER), where their folding is surveyed by the 170-kDa UDP-glucose:glycoprotein glucosyltransferase ...(UGGT). The enzyme acts as the single glycoprotein folding quality control checkpoint: it selectively reglucosylates misfolded glycoproteins, promotes their association with ER lectins and associated chaperones, and prevents premature secretion from the ER. UGGT has long resisted structural determination and sequence-based domain boundary prediction. Questions remain on how this single enzyme can flag misfolded glycoproteins of different sizes and shapes for ER retention and how it can span variable distances between the site of misfold and a glucose-accepting N-linked glycan on the same glycoprotein. Here, crystal structures of a full-length eukaryotic UGGT reveal four thioredoxin-like (TRXL) domains arranged in a long arc that terminates in two β-sandwiches tightly clasping the glucosyltransferase domain. The fold of the molecule is topologically complex, with the first β-sandwich and the fourth TRXL domain being encoded by nonconsecutive stretches of sequence. In addition to the crystal structures, a 15-Å cryo-EM reconstruction reveals interdomain flexibility of the TRXL domains. Double cysteine point mutants that engineer extra interdomain disulfide bridges rigidify the UGGT structure and exhibit impaired activity. The intrinsic flexibility of the TRXL domains of UGGT may therefore endow the enzyme with the promiscuity needed to recognize and reglucosylate its many different substrates and/or enable reglucosylation of N-linked glycans situated at variable distances from the site of misfold.
None of the current data processing pipelines for X-ray crystallography fragment-based lead discovery (FBLD) consults all the information available when deciding on the lattice and symmetry (i.e., ...the polymorph) of each soaked crystal. Often, X-ray crystallography FBLD pipelines either choose the polymorph based on cell volume and point-group symmetry of the X-ray diffraction data or leave polymorph attribution to manual intervention on the part of the user. Thus, when the FBLD crystals belong to more than one crystal polymorph, the discovery pipeline can be plagued by space group ambiguity, especially if the polymorphs at hand are variations of the same lattice and, therefore, difficult to tell apart from their morphology and/or their apparent crystal lattices and point groups. In the course of a fragment-based lead discovery effort aimed at finding ligands of the catalytic domain of UDP-glucose glycoprotein glucosyltransferase (UGGT), we encountered a mixture of trigonal crystals and pseudotrigonal triclinic crystals-with the two lattices closely related. In order to resolve that polymorphism ambiguity, we have written and described here a series of Unix shell scripts called
(
rystal p
lymorph
nd
igand
ikelihood-based
ssignment). The
scripts are written in Unix shell and use
for data processing,
/
and
for refinement, and
for ligand docking. The choice of the polymorph is effected by carrying out (in each of the known polymorphs) the tasks of diffraction data indexing, integration, scaling, and structural refinement. The most likely polymorph is then chosen as the one with the best structure refinement R
statistic. The
scripts further implement a likelihood-based ligand assignment strategy, starting with macromolecular refinement and automated water addition, followed by removal of the water molecules that appear to be fitting ligand density, and a final round of refinement after random perturbation of the refined macromolecular model, in order to obtain unbiased difference density maps for automated ligand placement. We illustrate the use of
to discriminate between H3 and P1 crystals used for an FBLD effort to find fragments binding to the catalytic domain of
UGGT.
Liposuction is one of the most common cosmetic surgery procedures around the world. Tumescent liposuction using local anesthesia has been shown to be the safest technique. Few long-term studies of ...results and satisfaction have been published on tumescent liposuction.
To evaluate long-term results and patient satisfaction of tumescent liposuction in a single-center institution.
Patients (n = 600) who had tumescent liposuction performed in our practice from 2002 to 2014 were contacted through letter, email, or phone to complete a questionnaire survey and in-office follow-up visit regarding their past liposuction procedures.
Thirty-two patients (n = 32) completed the patient questionnaire survey and followed up in the office. Surgeon and blinded evaluators saw significant differences in both the neck volume (surgeon evaluator: 2.42 vs. 0.71, p < .01; blinded evaluator: 2.8-1, p = .02) and Investigator Assessment Skin Laxity scales (blinded evaluator: 1.14 vs. 0.77, p < .01 for laxity and 1.33 vs. 0.75, p < .01 for firmness; surgeon evaluator: 1.17 vs. 0.83, p = .01 for laxity and 1.31 vs. 0.83; p < .01 for firmness). The mean follow-up period was 8.9 years overall and 9.9 years for the neck. Overall, 85.7% of the patients would recommend liposuction to their friends and family members.
Tumescent liposuction is a safe procedure with long-lasting results and high patient satisfaction.
Background/Objectives
U.S. adults and children are equally likely to have allergic contact dermatitis. Historically the narrow geographic location of data‐reporting providers has quantitatively and ...qualitatively limited the pediatric contact dermatitis data. The Pediatric Contact Dermatitis Registry was used to evaluate self‐identified pediatric patch test providers within the United States with regard to demographic characteristics, geographic location, and practice patterns.
Methods
A wide range of U.S. providers were invited to join the registry by completing a secure online 11‐question registration survey.
Results
There were 252 respondents from 50 states and the District of Columbia; 28.6% were pediatric dermatologists and members of the Society for Pediatric Dermatology (SPD), and 38% were members of the American Contact Dermatitis Society. The cumulative range of pediatric patch‐test evaluations performed each year was 1,726 to 4,613 children. SPD members had a significantly greater likelihood of performing a commercially available patch test (odds ratio 7.14 95% confidence interval 5.11, 9.97, p < .001) than those who were not SPD members. SPD members also had significantly lower odds of performing North American Contact Dermatitis Group standard tests than nonmembers.
Conclusions
The frequency of patch test evaluations in children is significantly underreported. This study provides insight into the practice patterns of various providers who are patch testing children and makes recommendations for evidence‐based modifications regarding these practices. Limitations of the study include survey responder selection bias and small sample size.
Laser resurfacing produces a controlled skin injury, resulting in a wound healing response. This wound healing response allows for collagen remodeling, which improves skin texture and tone. Topical ...agents are often employed following laser treatments to facilitate recovery. The introduction of newer small-molecule technologies allow for improved recovery and cosmesis.
We sought to perform a critical review of the safety and efficacy of newer small-molecule technologies employed following laser resurfacing.
We performed a PubMed search of the generic name of the following topicals and included literature relevant to laser procedures, with an emphasis on laser resurfacing: thermal spring water, conjugated linolenic acid, vitamin C/vitamin E/ferulic acid serum, tripeptide/hexapeptide technology-containing products, growth factor serum and gel, recombinant human epidermal growth factor ointment and gel, red deer umbilical cord lining mesenchymal stem cell extract cream and serum, silicone-based gel, and microparticulate (1-3, 1-6 beta-glucan) gel.
Our search of the PubMed database yielded 62 results, out of which 17 clinical studies were included in this publication. The majority of aforementioned topicals show promise in terms of improving post-resurfacing recovery or cosmesis.
Clinical data regarding these agents is limited by the number and quality of studies. It is therefore challenging to propose a recommendation supporting any particular topical. We provide our own provider-specific post-laser resurfacing protocols to offer insight regarding new small-molecule technologies.
There is increasing evidence that neuropeptides such as a substance P, neurotrophins or beta-endorphin, an endogenous agonist for mu-opioid receptor, are involved in the pathogenesis of atopic ...dermatitis in which mental stress and scratching deteriorate the disease. mu-Opioid receptor, a G-protein-coupled receptor, can be downregulated and internalized by agonists and other factors in vitro. In this study, we investigated the regulation of mu-opioid receptor and nerve endings in atopic dermatitis patients. Skin biopsies from atopic dermatitis patients revealed a significant downregulation of mu-opiate receptor expression in epidermis of atopic dermatitis. Permeabilization of the skin showed that the receptor in keratinocytes from atopic dermatitis is internalized. The mRNA expression pattern of the mu-opiate receptor is different in epidermis taken from patients with chronic atopic dermatitis compared to normal skin. In atopic dermatitis, the mRNA is concentrated in the subcorneal layers of the epidermis and in normal skin in the suprabasal layers. Staining of the nerve endings using protein gene product 9.5 shows a different pattern of epidermal nerve endings in normal skin compared to atopic dermatitis. In normal skin, the epidermal nerve endings are rather thick. However, in atopic dermatitis, the epidermal nerve endings are thin and run straight through the epidermis. Based on these observations and combining the 'intensity' and 'pattern' hypothesis, we propose a new theory especially for histamine-unrelated, peripheral induction of chronic pruritus. We suggest that 'itch' is elicited in the epidermal unmyelinated nerve C-fibers and 'pain' in the dermal unmyelinated nerve fibers. The downregulation of the opioid receptor in the epidermis contributes to the chronic itching. We call this new hypothesis the 'layer hypothesis'.
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