Cutaneous interaction with visible light: What do we know?

Visible light has been used therapeutically in dermatology for years for a variety of cosmetic and medical indications, including skin rejuvenation and the treatment of inflammatory and neoplastic conditions, among others. Until recently, visible light was thought to be relatively inert compared to its spectral neighbors, ultraviolet and infrared radiation. However, recent literature has described the ability of visible light to cause erythema in light skin and pigmentary changes in individuals with darker skin types. Concern surrounding its potentially damaging cutaneous effects has been raised in both the medical community and social media outlets. In this article, we provide an evidenced-based review describing what is currently known about visible light, focusing on its role in dermatologic diseases including disorders of hyperpigmentation such as melasma and postinflammatory hyperpigmentation.

Mohs micrographic surgery for verrucous carcinoma: a review of the literature.

Verrucous carcinoma is a rare, low grade variant of squamous cell carcinoma that rarely metastasizes but tends to display aggressive local behavior. Wide local excision is the most common treatment, but has high rates of local recurrence, ranging from 19 to 75% in the literature. The cases of verrucous carcinoma treated with Mohs micrographic surgery in the literature, as well as a previously unpublished case is summarized. PubMed was searched for terms related to verrucous carcinoma and Mohs micrographic surgery, and articles reporting cases of verrucous carcinoma treated with Mohs were reviewed and summarized. A previously unpublished case treated at our institution was also reported. Thirty-eight cases of verrucous carcinoma treated with Mohs surgery were analyzed. The average age of patients was 52.1, and 50% were male. The most common sites were the foot (47%) and the anogenital region (34%). Lesion duration ranged from 0.17 to 40 years with a mean of 4.8 years, and tumor diameter ranged from 1 to 10 cm with a mean of 4.6 cm. The local recurrence rate following Mohs was 16%, with nodal metastasis occurring in 3% and no cases of distant metastasis. As verrucous carcinoma demonstrates locally aggressive behavior and a high risk of local recurrence, Mohs micrographic surgery should be considered as first line treatment. Further research directly comparing wide local excision to Mohs surgery is needed.

Head Over Wheels: Traumatic Head and Neck Injuries Secondary to Mountain Biking.

OBJECTIVES: The popularity of mountain biking (MTB) in the United States has risen in recent years. We sought to identify the prevalence and distribution of MTB associated head and neck injuries presenting to emergency departments across the U.S. and identify risk factors for hospital admission in this patient population. METHODS: The National Electronic Injury Surveillance System (NEISS) was queried for MTB related injuries of the head and neck from 2009 to 2018, with analysis for incidence, age, gender, anatomic site, and diagnoses. RESULTS: A total of 486 cases were identified, corresponding to an estimated 18 952 head and neck MTB related ED visits. Patients were predominantly male (80.7%) and white (69.8%) with a median age of 35 years (interquartile range, 21-46 years). A majority (88.4%) of patients were released from the ED, but a significant proportion of patients were admitted (9.2%) or transferred (1.2%). The most common facial fractures were facial/not specified (35%), nasal bone (29%), mandible (15%), orbit (12%), and zygomaxillary complex (9%). The greatest predictors of hospital admission/transfer were injury to the mouth or neck and avulsion-type injury (P < .001). CONCLUSIONS: MTB results in a significant number of traumatic head and neck injuries nationwide. Patients are primarily adult, white males. The majority of injuries result in discharge from the ED, however a small amount of these patients experience significant morbidity necessitating hospital admission. Understanding the distribution of MTB head and neck injuries may aid in the clinical evaluation of these patients. LEVEL OF EVIDENCE: 4.

A Severe Presentation of Plasma Cell Cheilitis.

Plasma cell cheilitis (PCC) is an uncommon condition characterized by mature plasma cell infiltration of the dermis of the mucosal lip. The condition often presents as a red-brown patch or plaque on the lower lip in older individuals that can progress to erosions and edema. Diagnosis can be delayed because clinical findings are nonspecific and can mimic neoplastic, infectious, and inflammatory conditions. We describe a patient with PCC who presented to our institution via teledermatology. Findings were equivocal on 2 early biopsies until the presentation evolved to dramatic ulceration and necrosis, which prompted a third biopsy that was diagnostic for PCC. Empiric therapy with a class I topical corticosteroid was successful.

Breast Microsurgery in Plastic Surgery Literature: A 21-Year Analysis of Publication Trends.

Introduction Microsurgical reconstruction of the breast represents an area of continual evolution, as new autologous flaps are introduced and principles are refined. This progression can be demonstrated by bibliometric analysis of the scientific literature. Methods The top 10 plastic surgery journals were determined by impact factor (IF). Each issue of every journal from 1993 to 2013 was accessed directly, and all articles discussing microsurgery on the female breast were classified by authors' geographic location, study design, and level of evidence (LOE, I-V). The productivity index and productivity share of each geographic region was calculated based on number of articles published and IF. Results A total of 706 breast microsurgery articles were analyzed. There was a significant increase in microsurgical breast research (p < 0.01), with an average 33.6 ± 31.1 articles per year and a mean increase of 4.4 articles per year. Most research was of lower LOE, with level I constituting 0.14% and level II constituting 5.21% of all articles. United States contributed the most research with 336.4 articles, followed by Western Europe with 242.2. However, Western Europe experienced the greatest increase in productivity share, with + 0.50 ± 0.29 growth, while United States demonstrated the greatest decrease in productivity share with - 1.23 ± 0.31 growth. Among autologous flaps, transverse rectus abdominis muscle research had the greatest yearly publication volume until 2002, when overtaken by deep inferior epigastric perforator flap research. Conclusion Over the 21-year study period, the United States not only contributed the greatest volume of research on female breast microsurgery but also demonstrated the greatest decline in research productivity. Efforts should be made to increase the LOE in breast microsurgery research.

Characterization of the adaptive and innate immune response to intravenous oncolytic reovirus (Dearing type 3) during a phase I clinical trial.

There is an emerging realization from animal models that the immune response may have both detrimental and beneficial therapeutic effects during cancer virotherapy. However, there is a dearth of clinical data on the immune response to viral agents in patients. During a recently completed phase I trial of intravenous reovirus type 3 Dearing (RT3D), heavily pretreated patients with advanced cancers received RT3D at doses escalating from 1 x 10(8) tissue culture infectious dose-50 (TCID(50)) on day 1 to 3 x 10(10) TCID(50) on 5 consecutive days of a 4 weekly cycle. A detailed analysis of the immune effects was conducted by collecting serial clinical samples for analysis of neutralizing anti-reoviral antibodies (NARA), peripheral blood mononuclear cells (PBMC) and cytokines. Significant increases in NARA were seen with peak endpoint titres >1/10 000 in all but one patient. The median fold increase was 250, with a range of 9-6437. PBMC subset analysis showed marked heterogeneity. At baseline, CD3+CD4+ T cells were reduced in most patients, but after RT3D therapy their numbers increased in 47.6% of patients. In contrast, most patients had high baseline CD3+CD8+ T-cell levels, with 33% showing incremental increases after therapy. In some patients, there was increased cytotoxic T-cell activation post-therapy, as shown by increased CD8+perforin/granzyme+ T-cell numbers. Most patients had high numbers of circulating CD3-CD56+ NK cells before therapy and in 28.6% this increased with treatment. Regulatory (CD3+CD4+CD25+) T cells were largely unaffected by the therapy. Combined Th1 and Th2 cytokine expression increased in 38% of patients. These data confirm that even heavily pretreated patients are capable of mounting dynamic immune responses during treatment with RT3D, although these responses are not clearly related to the administered virus dose. These data will provide the basis for future studies aiming to modulate the immune response during virotherapy.

The immune system--is it relevant to cancer development, progression and treatment?

The ability of the immune system to effectively respond to human tumours is a matter of long-term controversy. There is an increasing body of recent evidence to support a role for the immune system in eliminating pre-clinical cancers, an old concept termed 'immunosurveillance'. 'Immunoediting' is an updated hypothesis, in which selection pressures applied by the immune response to tumours modulate tumour immunogenicity and growth. Tumour infiltration by immune cells has been shown to have powerful prognostic significance in a host of cancer types. Paradoxically, in some circumstances the immune system can promote tumour development. Cytotoxic therapies, including radiotherapy and chemotherapy, induce potentially immunogenic cell death, releasing tumour-associated antigens in the context of a 'danger' signal to the immune system. An understanding of the interaction between immune cells, tumour cells and treatment modalities will therefore guide the future combination of immunotherapy with conventional therapy to achieve optimal anti-tumour effects.

Social instability in adolescence alters the central and peripheral hypothalamic-pituitary-adrenal responses to a repeated homotypic stressor in male and female rats.

There has been little research on effects of chronic stressors on neuroendocrine function in adolescence despite increasing evidence of enduring effects of stressors during this period on behaviour in adulthood. We previously reported that social stress (SS: daily 1 h isolation and new cage partner for 16 days) in adolescence altered locomotor responses to psychostimulants in adulthood. Here, we investigated neuroendocrine responses over the duration of the procedure that may underlie the enduring effects of SS. SS rats were compared to rats undergoing daily isolation only (ISO) and controls (CTL) to determine responses to acute and repeated isolation with and without social instability. At 30 days of age (first isolation), higher plasma corticosterone and corticotrophin-releasing hormone (CRH) mRNA expression in the paraventricular nucleus (PVN) of the hypothalamus and in the central nucleus of the amygdala (CeA) were found in males caged with a new partner (SS) after isolation than those returned to their original partner (ISO). On day 45, SS males and females showed less habituation (higher bioactive levels of corticosterone based on plasma corticosterone and corticosteroid binding globulin levels) to the 16th episode of isolation than did ISO. SS and ISO had higher baseline expression of CRH mRNA in the PVN on day 45 than did CTL, and only CTL had increased levels after isolation. CRH mRNA expression in the CeA increased to a first isolation in CTL and to a 16th isolation in SS but not in ISO males. Modest differences in social interactions were observed between SS and ISO when returned to their cages after isolation. The results suggest that mild social stressors in adolescence impede neuroendocrine adaptation to homotypic stressors. The resultant increase in exposure to glucocorticoids over adolescence may alter ongoing brain development and increase vulnerability to psychopathology.

Fusogenic membrane glycoprotein-mediated tumour cell fusion activates human dendritic cells for enhanced IL-12 production and T-cell priming.

Fusogenic membrane glycoproteins (FMG) are a family of viral genes that, when expressed in tumour cells, trigger extensive cell to cell fusion and subsequent cell death. Gene therapy approaches using FMG are also potentially immunogenic, since syncitia generated ex vivo can be therapeutic as antitumour vaccines in murine models. This study has addressed the mechanisms responsible for the immunogenicity of FMG-mediated cell death, and its applicability to human immune priming. We show that fusion of human Mel888 melanoma cells following transfection with FMG can reverse the suppressive effects of Mel888 on dendritic cells (DC) phenotype, and potentiate IL-12 production by DC on activation in a cell contact-dependent manner. DC loaded with fusing, but not intact, tumour cells primed a naive, tumour-specific cytotoxic T-cell response, which was MHC class I-restricted and associated with production of high levels of IFNgamma and, later, IL-5. Fusing cells were an effective source of antigen for DC cross-priming and presentation of the melanoma-specific antigen gp100 to a specific T-cell clone. These data show, in a human system, that FMG represent an immunogenic, as well as cytotoxic, gene therapy for cancer, reversing the inhibitory effects of tumour cells on DC to potentiate IL-12 production and naive T-cell priming.

Immunosuppressive effects of radiation on human dendritic cells: reduced IL-12 production on activation and impairment of naive T-cell priming.

Dendritic cells (DC) are professional antigen-presenting cells (APC) of the immune system, uniquely able to prime naive T-cell responses. They are the focus of a range of novel strategies for the immunotherapy of cancer, a proportion of which include treating DC with ionising radiation to high dose. The effects of radiation on DC have not, however, been fully characterised. We therefore cultured human myeloid DC from CD14+ precursors, and studied the effects of ionising radiation on their phenotype and function. Dendritic cells were remarkably resistant against radiation-induced apoptosis, showed limited changes in surface phenotype, and mostly maintained their endocytic, phagocytic and migratory capacity. However, irradiated DC were less effective in a mixed lymphocyte reaction, and on maturation produced significantly less IL-12 than unirradiated controls, while IL-10 secretion was maintained. Furthermore, peptide-pulsed irradiated mature DC were less effective at naive T-cell priming, stimulating fewer effector cells with lower cytotoxicity against antigen-specific targets. Hence irradiation of DC in vitro, and potentially in vivo, has a significant impact on their function, and may shift the balance between T-cell activation and tolerization in DC-mediated immune responses.

Radiation-induced cell death and dendritic cells: potential for cancer immunotherapy?

Dendritic cells are key orchestrators of the immune system. There is considerable interest in their use for treating cancer. Whether they initiate an effective cytotoxic response against antigen-bearing cells, or produce tolerance, depends on the context in which those antigens are presented. Ionising radiation, and the cell death it causes, has several properties that may facilitate such an effective response. A range of in-vitro and in-vivo data supports this, although potential problems exist that may require concurrent strategies.

FGFR3IIIS: a novel soluble FGFR3 spliced variant that modulates growth is frequently expressed in tumour cells.

Fibroblast growth factor receptor 3 (FGFR3) is one of four high-affinity tyrosine kinase receptors for the FGF family of ligands, frequently associated with growth arrest and induction of differentiation. The extracellular immunoglobulin (IgG)-like domains II and III are responsible for ligand binding; alternative usage of exons IIIb and IIIc of the Ig-like domain III determining the ligand-binding specificity of the receptor. By reverse transcriptase polymerase chain reaction (RT-PCR) a novel FGFR3IIIc variant FGFR3IIIS, expressed in a high proportion of tumours and tumour cell lines but rarely in normal tissues, has been identified. Unlike recently described nonsense transcripts of FGFR3, the coding region of FGFR3IIIS remains in-frame producing a novel protein. The protein product is coexpressed with FGFR3IIIc in the membrane and soluble cell fractions; expression in the soluble fraction is decreased after exposure to bFGF but not aFGF. Knockout of FGFR3IIIS using antisense has a growth-inhibitory effect in vitro, suggesting a dominant-negative function for FGFR3IIIS inhibiting FGFR3-induced growth arrest. In summary, alternative splicing of the FGFR3 Ig-domain III represents a mechanism for the generation of receptor diversity. FGFR3IIIS may regulate FGF and FGFR trafficking and function, possibly contributing to the development of a malignant phenotype.

Do androgens influence hair growth by altering the paracrine factors secreted by dermal papilla cells?

Androgens regulate many aspects of human hair growth in both sexes. After puberty they transform tiny vellus follicles in many areas, e.g. the face, to terminal ones producing long, thick, pigmented hairs. In genetically predisposed individuals, androgens also cause the reverse transformation of terminal scalp follicles into vellus ones, causing balding. In the current hypothesis for androgen action, androgens control most follicular cells indirectly acting via the mesenchyme-derived dermal papilla which regulates many aspects of follicular activity. In this model androgens binding to androgen receptors in dermal papilla cells alter their production of regulatory molecules which influence other follicular components; these molecules may be soluble paracrine factors and/or extracellular matrix proteins. This hypothesis is supported by immunohistochemical localisation of androgen receptors in dermal papilla cell nuclei and the demonstrations that androgen receptor content and testosterone metabolism patterns of cultured dermal papilla cells from various body sites reflect hair growth in androgen-insensitivity syndromes. The next question is whether androgens alter the paracrine factors secreted by dermal papilla cells. Cultured dermal papilla cells do release soluble, proteinaceous factors into their media which stimulate the growth of keratinocytes and other dermal papilla cells. This mitogenic potential can cross species from humans to rodents. Importantly, testosterone in vitro stimulates the mitogenic potential of beard cells, but in contrast inhibits production by balding scalp cells reflecting their in vivo androgenic responses. Since androgens in vitro do alter the secretion of paracrine factors the current focus lies in identifying specific factors produced, e.g. IGF-I and stem cell factor (SCF), using ELISA and RT-PCR, and comparing their expression in cells from follicles with varying responses to androgens in vivo or under androgen stimulation in vitro. This should lead to greater understanding of androgen action and enable the development of better treatment for androgen-potentiated disorders.

Anatomy of the muscular subpulmonary infundibulum with regard to the Ross procedure.

BACKGROUND: To clarify the precise anatomical relationship of the muscular subpulmonary infundibulum. METHODS: Eleven hearts were dissected, and microscopic sections taken through the arterial trunks of a 37-week-old fetus and of a neonate. The anatomy was also investigated during operative Ross procedures. RESULTS: The sinotubular junctions of the pulmonary and aortic roots cross obliquely. The leaflets of the pulmonary valve are lifted away from the ventricular septum by the free-standing subpulmonary infundibulum, whereas the aortic valve is deeply wedged between the atrioventricular junctions. The muscular infundibulum spirals around the aortic root, being longest below the right-facing aortic sinus and shortest below the left. The first septal perforating artery pierces the septum below the shortest part of the infundibulum, sometimes within a millimeter of the pulmonary valvar hinge, but a muscular sleeve lifts the pulmonary leaflets from the septal musculature. CONCLUSIONS: The pulmonary valvar leaflets are supported entirely by free-standing musculature, having no direct relationship with the ventricular septum. This makes possible the Ross procedure.

The hair follicle: a paradoxical androgen target organ.

Androgens are the main regulator of normal human hair growth. After puberty, they promote transformation of vellus follicles, producing tiny, unpigmented hairs, to terminal ones, forming larger pigmented hairs, in many areas, e.g. the axilla. However, they have no apparent effect on the eyelashes, but can cause the opposite transformation on the scalp leading to the replacement of terminal hairs by vellus ones and the gradual onset of androgenetic alopecia. This paradox appears to be an unique hormonal effect. Hair follicles are mainly epithelial tissues, continuous with the epidermis, which project into the dermis. A mesenchyme-derived dermal papilla enclosed within the hair bulb at the base controls many aspects of follicle function. In the current hypothesis for androgen regulation, the dermal papilla is also considered the main site of androgen action with androgens from the blood binding to receptors in dermal papilla cells of androgen-sensitive follicles and causing an alteration of their production of paracrine factors for target cells e.g. keratinocytes. Studies of cultured dermal papilla cells from sites with different responses to androgens in vivo have confirmed the paradoxical responses. All dermal papilla cells from androgen-sensitive sites contain low capacity, high affinity androgen receptors. However, only some cells formed 5alpha-dihydrotestosterone, e.g. beard but not axillary cells, in line with hair growth in 5alpha-reductase deficiency. Incubation with androgens also stimulated the mitogenic capacity of beard cell media, but inhibited that produced by scalp cells. This suggests that the paradoxical differences are due to differential gene expression within hair follicles, presumably caused during embryogenesis.

Management of ventricular septal defect: a survey of practice in the United Kingdom.

BACKGROUND: A survey of pediatric cardiac surgeons was performed to establish current opinions in the United Kingdom concerning closure of ventricular septal defect. METHODS: Questionnaires were sent to 14 pediatric cardiac centers in 1995 (16 surgeons, 100% response), and again in 1997 (20 surgeons, 100% response). RESULTS: Results are presented for 1997, with findings from 1995 shown in parentheses. Eleven (6) surgeons used bypass exclusively, 9 (10) sometimes used circulatory arrest. Operative techniques were similar, although the material used for the patch varied. Multiple defects were approached via the transatrial route by 18 (15), right ventriculotomy by 11 (7) and left ventriculotomy by 7 (6). The juxta-arterial defect was approached via the transpulmonary route by 16 (13), a combination by 9 (11), transatrial by 10 (6), and transventricular by 9 (5). The most common indications for pulmonary arterial banding were "Swiss cheese" defect for 13 (13), and functionally single ventricle for 5 (6). Ventricular septal defect associated with coarctation was repaired in two stages by 13 (10), a single stage by 5 (3), or either by 1 (3). CONCLUSIONS: Pediatric cardiac surgeons in the United Kingdom demonstrate a uniform, evidence-based approach to the management of ventricular septal defect.

Organ culture of arteries for experimental studies of vascular endothelium in situ.

The objective of this study was to determine whether organ culture of arteries could be used as a more physiological model than endothelial cell culture for the study of vascular endothelium in vitro. Small pieces of artery from rat, pig, piglet and man were cultured in 24-well plates for up to seven or eight days to study the characteristics of the vascular endothelial cell layer during the first week of culture, in particular its integrity, viability and propensity for cell division. Using conventional and confocal microscopy, silver-stained endothelial cell boundaries were shown to be intact at all time points, up to and including day 7. However, occasional very small gaps between endothelial cells were seen with the scanning electron microscope under high power at day 7. Using the bromodeoxyuridine technique, no endothelial cell division was seen at day 4 in any species, except for the occasional endothelial cell in rat aorta. At day 7, pig, piglet and human arteries showed only very occasional dividing endothelial cells, but many endothelial cells had divided by day 7 in rat aorta. Viability of the endothelium was assessed using fluorochromes and examination of the endothelial layer en face using confocal microscopy. Viability was always excellent (> 95%) up to day 4. By day 7, occasional patches of dead cells could be seen, which were most obvious in rat aorta. This study demonstrates that endothelial cells can be studied in situ in organ culture with intact morphology, lack of cell division and excellent viability for a minimum of four days. For many research questions involving vascular endothelium--for example the pathophysiology of hyperacute rejection--short-term organ culture of vessels is likely to represent a more physiological model than endothelial cell culture.

Comparison of adenovirus gene transfer to vascular endothelial cells in cell culture, organ culture, and in vivo.

A replication-defective adenovirus 5 vector carrying the beta-galactosidase reporter gene was tested for its efficiency for gene delivery to vascular endothelial cells in various situations. Both porcine and human primary vascular endothelial cell cultures were very efficiently infected (>90%) at adenovirus concentrations of 10(10) pfu/ml or higher. Cultured rat fibroblasts and keratinocytes were even more readily infected, with >90% infection with adenovirus titers of 10(8) pfu/ml or higher. However, nondividing vascular endothelium in situ was very poorly transduced. Pieces of aorta from adult pigs, sheep, rabbit and rat, and pieces of human umbilical artery and vein were studied in organ culture. These showed only occasional positive vascular endothelial cells when exposed to the adenovirus vector at concentrations up to 5x10(11) pfu/ml. Kidney perfusion studies in rats and pigs gave similar results. The only exception to the above findings was in very young (3-4 day old) piglets, which showed excellent (>90%) infection of vascular endothelium with the adenovirus vector at titers of 10(10) pfu/ml. Our data suggest that adenovirus vectors will not be of value for gene delivery to uninjured vascular endothelium in situ, and are therefore unsuited for ex vivo genetic manipulation of vascular endothelium in organs for transplantation.