Neutrophilic Dermatoses and Their Implication in Pathophysiology of Asthma and Other Respiratory Comorbidities: A Narrative Review.

Neutrophilic dermatoses (ND) are a polymorphous group of noncontagious dermatological disorders that share the common histological feature of a sterile cutaneous infiltration of mature neutrophils. Clinical manifestations can vary from nodules, pustules, and bulla to erosions and ulcerations. The etiopathogenesis of neutrophilic dermatoses has continuously evolved. Accumulating genetic, clinical, and histological evidence point to NDs being classified in the spectrum of autoinflammatory conditions. However, unlike the monogenic autoinflammatory syndromes where a clear multiple change in the inflammasome structure/function is demonstrated, NDs display several proinflammatory abnormalities, mainly driven by IL-1, IL-17, and tumor necrosis factor-alpha (TNF-a). Additionally, because of the frequent association with extracutaneous manifestations where neutrophils seem to play a crucial role, it was plausible also to consider NDs as a cutaneous presentation of a systemic neutrophilic condition. Neutrophilic dermatoses are more frequently recognized in association with respiratory disorders than by chance alone. The combination of the two, particularly in the context of their overlapping immune responses mediated primarily by neutrophils, raises the likelihood of a common neutrophilic systemic disease or an aberrant innate immunity disorder. Associated respiratory conditions can serve as a trigger or may develop or be exacerbated secondary to the uncontrolled skin disorder. Physicians should be aware of the possible pulmonary comorbidities and apply this knowledge in the three steps of patients' management, work-up, diagnosis, and treatment. In this review, we attempt to unravel the pathophysiological mechanisms of this association and also present some evidence for the role of targeted therapy in the treatment of both conditions.

Fasting and Its Impact on Skin Anatomy, Physiology, and Physiopathology: A Comprehensive Review of the Literature.

Skin serves as the first protective line and barrier of the body. Like many other organs, skin can be affected by several disorders in response to external factors such as pathogens, ultraviolet light, and pollution, as well as endogenous alterations related to aging and/or oxidative stress disturbance. Researchers have reported new insights into how skin cells are altered in response to caloric restriction diets in mammals. One of the most well-known caloric restriction diets is the Ramadan intermittent fasting, which is a radical change in the diet plan of practitioners for the period of one lunar month. Ramadan fasting represents the fourth of the five pillars of the Islamic creed. Even though infirm individuals are waived to take part in this religious duty, patients with various health problems, including those with different skin disorders, might choose to share this event with peers and family members. No standardized protocols or guidelines exist, however, to advise their physicians on the proper management of their patients' condition during fasting. With an increasing Muslim population living in Western countries, this topic has started to draw substantial attention, not only of Middle-Eastern physicians, but also of clinicians in the West. For this purpose, we carried out a comprehensive overview on the topic. Our main findings are that: (1) there is a strong need for evidence-based suggestions and guidance. Literature on the impact of the Ramadan fasting, as well as of other kinds of fasting, on skin diseases is scarce and of poor quality, as well as the information available from the Internet; (2) patients willing to fast should be advised about the importance of taking proper treatments or consider alternative options including administration of trans-dermal/topical drugs, as they are permitted during daylight hours. Further, non-compliance has important, clinical and economic implications for an effective patient management.

Connexin 47 mutations increase risk for secondary lymphedema following breast cancer treatment.

PURPOSE: Secondary lymphedema is a frequent complication of breast cancer associated with surgery, chemotherapy, or radiation following breast cancer treatment. The potential contribution of genetic susceptibility to risk of developing secondary lymphedema following surgical trauma, radiation, and other tissue insults has not been studied. EXPERIMENTAL DESIGN: To determine whether women with breast cancer and secondary lymphedema had mutations in candidate lymphedema genes, we undertook a case-control study of 188 women diagnosed with breast cancer recruited from the University of Pittsburgh Breast Cancer Program (http://www.upmccancercenter.com/breast/index.cfm) between 2000 and 2010. Candidate lymphedema genes, GJC2 (encoding connexin 47 [Cx47]), FOXC2, HGF, MET, and FLT4 (encoding VEGFR3), were sequenced for mutation. Bioinformatics analysis and in vitro functional assays were used to confirm significance of novel mutations. RESULTS: Cx47 mutations were identified in individuals having secondary lymphedema following breast cancer treatment but not in breast cancer controls or normal women without breast cancer. These novel mutations are dysfunctional as assessed through in vitro assays and bioinformatics analysis and provide evidence that altered gap junction function leads to lymphedema. CONCLUSIONS: Our findings challenge the view that secondary lymphedema is solely due to mechanical trauma and support the hypothesis that genetic susceptibility is an important risk factor for secondary lymphedema. A priori recognition of genetic risk (i) raises the potential for early detection and intervention for a high-risk group and (ii) allows the possibility of altering surgical approach and/or chemo- and radiation therapy, or direct medical treatment of secondary lymphedema with novel connexin-modifying drugs.

GJC2 missense mutations cause human lymphedema.

Lymphedema is the clinical manifestation of defects in lymphatic structure or function. Mutations identified in genes regulating lymphatic development result in inherited lymphedema. No mutations have yet been identified in genes mediating lymphatic function that result in inherited lymphedema. Survey microarray studies comparing lymphatic and blood endothelial cells identified expression of several connexins in lymphatic endothelial cells. Additionally, gap junctions are implicated in maintaining lymphatic flow. By sequencing GJA1, GJA4, and GJC2 in a group of families with dominantly inherited lymphedema, we identified six probands with unique missense mutations in GJC2 (encoding connexin [Cx] 47). Two larger families cosegregate lymphedema and GJC2 mutation (LOD score = 6.5). We hypothesize that missense mutations in GJC2 alter gap junction function and disrupt lymphatic flow. Until now, GJC2 mutations were only thought to cause dysmyelination, with primary expression of Cx47 limited to the central nervous system. The identification of GJC2 mutations as a cause of primary lymphedema raises the possibility of novel gap-junction-modifying agents as potential therapy for some forms of lymphedema.

Effects of HTR1A C(-1019)G on amygdala reactivity and trait anxiety.

CONTEXT: Serotonin 1A (5-hydroxytryptamine 1A [5-HT(1A)]) autoreceptors mediate negative feedback inhibition of serotonergic neurons and play a critical role in regulating serotonin signaling involved in shaping the functional response of major forebrain targets, such as the amygdala, supporting complex behavioral processes. A common functional variation (C[-1019]G) in the human 5-HT(1A) gene (HTR1A) represents 1 potential source of such interindividual variability. Both in vitro and in vivo, -1019G blocks transcriptional repression, leading to increased autoreceptor expression. Thus, -1019G may contribute to relatively decreased serotonin signaling at postsynaptic forebrain target sites via increased negative feedback. OBJECTIVES: To evaluate the effects of HTR1A C(-1019)G on amygdala reactivity and to use path analyses to explore the impact of HTR1A-mediated variability in amygdala reactivity on individual differences in trait anxiety. We hypothesized that -1019G, which potentially results in decreased serotonin signaling, would be associated with relatively decreased amygdala reactivity and related trait anxiety. DESIGN: Imaging genetics in participants from an archival database. PARTICIPANTS: Eighty-nine healthy adults. RESULTS: Consistent with prior findings, -1019G was associated with significantly decreased threat-related amygdala reactivity. Importantly, this effect was independent of that associated with another common functional polymorphism that affects serotonin signaling, 5-HTTLPR. While there were no direct genotype effects on trait anxiety, HTR1A C(-1019)G indirectly predicted 9.2% of interindividual variability in trait anxiety through its effects on amygdala reactivity. CONCLUSIONS: Our findings further implicate relatively increased serotonin signaling, associated with a genetic variation that mediates increased 5-HT(1A) autoreceptors, in driving amygdala reactivity and trait anxiety. Moreover, they provide empirical documentation of the basic premise that genetic variation indirectly affects emergent behavioral processes related to psychiatric disease risk by biasing the response of underlying neural circuitries.

Divergent effects of genetic variation in endocannabinoid signaling on human threat- and reward-related brain function.

BACKGROUND: Fatty acid amide hydrolase (FAAH) is a key enzyme in regulating endocannabinoid (eCB) signaling. A common single nucleotide polymorphism (C385A) in the human FAAH gene has been associated with increased risk for addiction and obesity. METHODS: Using imaging genetics in 82 healthy adult volunteers, we examined the effects of FAAH C385A on threat- and reward-related human brain function. RESULTS: Carriers of FAAH 385A, associated with reduced enzyme and possibly increased eCB signaling, had decreased threat-related amygdala reactivity but increased reward-related ventral striatal reactivity in comparison with C385 homozygotes. Similarly divergent effects of FAAH C385A genotype were manifest at the level of brain-behavior relationships. The 385A carriers showed decreased correlation between amygdala reactivity and trait anxiety but increased correlation between ventral striatal reactivity and delay discounting, an index of impulsivity. CONCLUSIONS: Our results parallel pharmacologic and genetic dissection of eCB signaling, are consistent with the psychotropic effects of Delta(9)-tetrahydrocannabinol, and highlight specific neural mechanisms through which variability in eCB signaling impacts complex behavioral processes related to risk for addiction and obesity.

Candidate gene analysis in primary lymphedema.

BACKGROUND: Primary lymphedema, the accumulation of protein-rich fluid in the interstitial space, is the clinical manifestation of mutations involved in lymphatic development and function. Mutations in three genes, VEGFR3, FOXC2, and SOX18, cause primary lymphedema. However, mutations in these three genes only account for a fraction of primary lymphedema. To identify other genes mutated in primary lymphedema, we resequenced twenty-five biologically plausible candidate genes for lymphedema in a large collection of primary lymphedema families. METHODS AND RESULTS: Candidate genes were selected on the basis of gene expression in lymphatic endothelial cells, differential antigenic expression in lymphatics, and mouse studies of lymphatic development. The gene sequence was downloaded from GenBank and sequence primers designed to amplify 1 Kb of the 5' sequence, exons and flanking intron-exon boundaries, and 500 bp of the UTR of each gene. No common causative mutations were observed among the 25 genes screened. Single mutations were observed in elastin microfibril interfacer (EMILIN1), lymphocyte cytosolic protein 2 (LCP2), fatty acid binding protein 4 (FABP4), protein tyrosine kinase SYK (SYK), neuropilin-2 (NRP2), SpSRY-box 17 (SOX17), vascular cell adhesion molecule 1 (VCAM1), ROR orphan receptor C (RORC), and vascular endothelial growth factor B (VEGFB). Among these, the mutations in EMILIN1, RORC, LCP2, SYK, and VEGFB failed to segregate with lymphedema. The mutations in FABP4 (2), NRP2, SOX17, and VACM1 are consistent with being causative mutations, but occur in families too small to convincingly confirm cosegregation of mutation and phenotype. CONCLUSION: We excluded mutation in 21 biological candidate genes as a common cause of primary lymphedema. Mutations in FABP4, NRP2, SOX17 and VCAM1 are consistent with causality and follow up of these four genes are warranted. The evidence for FABP4 harboring lymphedema mutations is discussed.

HGF and MET mutations in primary and secondary lymphedema.

BACKGROUND: Lymphedema is the abnormal accumulation of protein-rich fluid in the interstitial space. Primary lymphedema is a rare genetic condition with both autosomal dominant and autosomal recessive modes of inheritance. Three genes, FLT4 (VEGFR3), FOXC2, and SOX18 cause varying forms of primary lymphedema. In industrialized countries, secondary lymphedema is usually associated with cancer therapy and/or trauma. Recent observations suggested that hepatocyte growth factor/high affinity hepatocyte growth factor receptor (HGF/MET) were new candidate lymphedema genes. METHODS AND RESULTS: The coding exons and flanking regions of HGF and MET were directly sequenced in 145 lymphedema probands, 59 unrelated women with secondary lymphedema following treatment for breast cancer, 21 individual patients with lymphedema and intestinal lymphangiectasia, and at least 159 unrelated ethnic matched control individuals. Mutations leading to truncation or missense changes in evolutionarily conserved residues of HGF and MET were identified. These mutations were not polymorphic in control individuals. CONCLUSIONS: The identification of HGF/MET mutations in primary lymphedema, lymphedema/lymphangiectasia, and breast cancer-associated secondary lymphedema suggests that the HGF/MET pathway is causal or alters susceptibility for a broad range of lymphedema phenotypes. The HGF/MET pathway provides a new target for the prevention and/or treatment of lymphedema.

Paroxetine: population pharmacokinetic analysis in late-life depression using sparse concentration sampling.

AIM: To develop a population pharmacokinetic (PK) model using sparse sampling of long-term treatment with paroxetine in elderly depressed subjects, incorporating CYP2D6 genotype as well as other covariates. METHODS: Elderly subjects (age>or=70 years) with nonpsychotic, nonbipolar major depressive disorder from the inpatient and outpatient clinic were treated with paroxetine in a 5-year clinical trial investigating 'Maintenance Therapies in Late-Life Depression' (MTLD-2). Plasma concentrations were collected during regular visits. CYP2D6 genotype was determined using polymerase chain reaction (PCR) for each individual. A nonlinear mixed-effects model was developed with NONMEM for these subjects who received 10-40 mg day-1 of paroxetine during treatment. One- and two-compartment models with linear and nonlinear elimination (Michaelis-Menten) were evaluated. PK parameters as well as interindividual and residual variability were estimated. The effects of age, weight, sex, race and CYP2D6 genotypes on the pharmacokinetics of paroxetine were evaluated. RESULTS: One hundred and seventy-one subjects with a mean age of 77 years (range 69-95) and a mean weight of 72.0 kg (range 32.9-137.0) were enrolled in the MTLD-2 clinical trial. A total of 1970 paroxetine concentrations were available for population PK analyses. Approximately 10 samples were taken per subject. A two-compartment nonlinear PK model with additive and proportional error provided the best base model for description of the data. Weight and CYP2D6 polymorphisms were found to have a significant effect on maximal velocity (Vm), whereas sex had an effect on volume of distribution of the central compartment. The Vm estimates in each of the CYP2D6 phenotypic groups were: 125 microg h-1 in poor metabolizer (n=1), 182 microg h-1 in intermediate metabolizers (n=28), 454 microg h-1 in extensive metabolizers (n=36) and 3670 microg h-1 in ultra-rapid metabolizers (n=5). CONCLUSIONS: The population PK model adequately described paroxetine data in this elderly depressed population. The data indicate that female and male subjects with different CYP2D6 polymorphisms have different elimination rates and therefore may need to be dosed differently based on metabolizer genotype.

Decreased STAT1 expression by promoter methylation in squamous cell carcinogenesis.

BACKGROUND: Dysregulation of signal transducers and activators of transcription (STATs) is associated with many cancers, but no role of STAT1 in human tumor progression has been demonstrated. METHODS: We compared STAT1 protein expression in squamous cell carcinoma of the head and neck (SCCHN) tumors (n = 28) and normal oropharyngeal mucosa samples (n = 10) from patients without cancer as assessed by immunoblotting. Stable clones were established from SCCHN 1483 cells that were transfected with a STAT1 expression construct; cell growth and cisplatin-induced apoptosis of the clones and vector control-transfected 1483 cells were compared using trypan blue exclusion and Annexin V staining and expression of the cyclin-dependent kinase inhibitor p21 was assayed by immunoblotting. The growth of STAT1-overexpressing SCCHN 1483 xenograft tumors was compared with that of xenograft tumors derived from cells transfected with vector control DNA. DNA from SCCHN tumors (n = 16) and paired peripheral blood lymphocytes were analyzed for STAT1 mutations and promoter methylation using methylation-specific polymerase chain reaction and bisulfite sequencing. SCCHN cell lines (PCI-15b, 1483, and UM-22B) were treated with the demethylating agent azacytidine alone or in combination with the cytotoxic drug cisplatin, and expression of STAT1 and p21 were monitored by immunoblotting. All statistical tests were two-sided. RESULTS: STAT1 levels were statistically significantly lower in the SCCHN tumors than normal mucosa (median = 0.8 relative units versus 2.4, difference = 1.6, 95% confidence interval [CI] = 1.3 to 2.0, P < .001). Overexpression of STAT1 abrogated the growth of SCCHN cells and xenograft tumors and increased p21 expression. STAT1 expression levels of the tumors with STAT1 promoter methylation (n = 12) were lower than those of tumors (n = 4) without promoter methylation of STAT1 (P = .008). Azacytidine treatment increased expression of STAT1 and p21 in SCCHN cell lines and increased apoptosis in cisplatin-treated 1483 cells compared with cisplatin treatment alone (mean = 61.3% versus 25.8%, difference = 35.5%, 95% CI = 24.5% to 43.4%; P = .028). CONCLUSION: STAT1 can function as a tumor suppressor in SCCHN cells. Silencing of the STAT1 gene via promoter methylation may contribute to SCCHN tumor cell growth.

Lymphedema-distichiasis syndrome and FOXC2 gene mutation.

PURPOSE: To describe the clinical characteristics of a family with autosomal dominant lymphedema-distichiasis syndrome and to report the results of analysis of the FOXC2 gene DESIGN: Observational and experimental study. METHODS: The setting was a clinical practice. The study population was 17 members of a family with lymphedema-distichiasis. Observation procedures were complete ophthalmologic examinations and collection of blood samples. DNA was extracted. Mutation analysis of the coding region of the FOXC2 gene was performed using direct sequencing of polymerase chain reaction (PCR) product and a restriction enzyme assay. The main outcome measure was inheritance of mutation in FOXC2 gene. RESULTS: Nine patients had distichiasis or lymphedema or both and eight did not. Sequencing of the coding region of the only translated exon of the FOXC2 gene revealed a C to A transversion at position 939 resulting in a Tyr313Stop codon with premature termination of translation and a truncated protein product. The mutation was present in all nine affected individuals and in an asymptomatic 9-year-old boy. CONCLUSIONS: Distichiasis-lymphedema syndrome results from mutations in FOXC2, a member of the forkhead/winged family of transcription factors. There is intrafamilial variation in the clinical expression of the mutation.