ABSTRACT
BACKGROUND: Papillon-Lefévre syndrome (PLS; OMIM 245000) and Haim-Munk syndrome (HMS; OMIM 245010), which are both characterized by palmoplantar hyperkeratosis and periodontitis, are phenotypic variants of the same disease caused by mutations of the cathepsin C (CTSC) gene. AIM: To identify putative genetic modifying factors responsible for the differential development of the PLS or HMS phenotypes, we investigated two Hungarian patients with different phenotypic variants (PLS and HMS) but carrying the same homozygous nonsense CTSC mutation (c.748C/T; p.Arg250X). METHODS: To gain insights into phenotype-modifying associations, whole exome sequencing (WES) was performed for both patients, and the results were compared to identify potentially relevant genetic modifying factors. RESULTS: WES revealed two putative phenotype-modifying variants: (i) a missense mutation (rs34608771) of the SH2 domain containing 4A (SH2D4A) gene encoding an adaptor protein involved in intracellular signalling of cystatin F, a known inhibitor of the cathepsin protein, and (ii) a missense variant (rs55695858) of the odorant binding protein 2A (OBP2A) gene, influencing the function of the cathepsin protein through the glycosyltransferase 6 domain containing 1 (GLT6D1) protein. CONCLUSION: Our study contributes to the accumulating evidence supporting the clinical importance of phenotype-modifying genetic factors, which have high potential to aid the elucidation of genotype-phenotype correlations and disease prognosis.
Subject(s)
Acro-Osteolysis/genetics , Cathepsin C/genetics , Mutation, Missense , Papillon-Lefevre Disease/genetics , Phenotype , DNA Mutational Analysis , Female , Humans , Male , Polymorphism, Single Nucleotide , Signal TransductionABSTRACT
BACKGROUND: Pityriasis rubra pilaris (PRP) is a rare chronic inflammatory dermatosis with multifactorial aetiology. It is known that particular caspase recruitment domain family member 14 (CARD14) gene mutations are associated with familial PRP and certain forms of psoriasis. Additionally, few data are available about the role of CARD14 gene variants in sporadic PRP. The clinical picture is variable for the different types of PRP, therefore choosing the adequate treatment is often difficult, furthermore there are no specific guidelines for therapy. OBJECTIVE: Our aim was to survey the efficacy of the applied therapies and to screen the CARD14 gene variants in our PRP patients. METHODS: In this retrospective study, patients diagnosed with PRP between 2006 and 2016 at our clinic were involved. Besides the follow-up study of the treatments, the genetic analysis of CARD14 gene was performed. RESULTS: We analysed 19 patients, among whom 17 were diagnosed with type I, one with type III, and one with type V PRP. The majority of the patients were successfully treated with acitretin in combination with systemic corticosteroids, and the remaining patients were treated with other systemic therapies with diverse effects. The genetic screening of CARD14 gene revealed two previously described mutations (rs114688446, rs117918077) and six polymorphisms (rs28674001, rs2066964, rs34367357, rs11653893, rs11652075, rs2289541). Ten of 19 patients carried different CARD14 genetic variants either alone or in combination. CONCLUSION: Based on our experience, we propose that acitretin and an initial combination of short-term systemic corticosteroid therapy could be a successful treatment option for PRP. Although we identified several CARD14 variants in almost half of our cases, we did not find a correlation between the therapeutic response and the genetic background. Our data support the previous observation that CARD14 genetic variants are not specific to PRP, although they may indicate chronic inflammation.
Subject(s)
CARD Signaling Adaptor Proteins/genetics , Guanylate Cyclase/genetics , Membrane Proteins/genetics , Pityriasis Rubra Pilaris/genetics , Pityriasis Rubra Pilaris/therapy , Adult , Aged , Child , Dermatologic Agents/therapeutic use , Female , Follow-Up Studies , Genetic Testing , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Retrospective Studies , Skin CreamABSTRACT
Neurofibromatosis type 1 (NF1; OMIM 162200), a dominantly inherited multitumor syndrome, results from mutations in the Neurofibromin 1 (NF1) gene. We present the case of a Hungarian woman with the clinical phenotype of NF1 over her whole body and the clinical features of unilateral overgrowth involving her entire left leg. This unusual phenotype suggested either the atypical form of NF1 or the coexistence of NF1 and overgrowth syndrome. Direct sequencing of the genomic DNA isolated from peripheral blood revealed a novel frameshift mutation (c.5727insT, p.V1909fsX1912) in the NF1 gene. Next-generation sequencing of 50 oncogenes and tumour suppressor genes, performed on the genomic DNAs isolated from tissue samples and peripheral blood, detected only wild-type sequences. Based on these results, we concluded that the patient is affected by an unusual phenotype of NF1, and that the observed unilateral overgrowth of the left leg might be a rare consequence of the identified c.5727insT mutation.
Subject(s)
Frameshift Mutation , Hypertrophy/genetics , Leg/pathology , Neurofibromatosis 1/genetics , Diagnosis, Differential , Female , Humans , Hypertrophy/diagnosis , Middle Aged , Neurofibromatosis 1/diagnosis , Pedigree , PhenotypeABSTRACT
The EDA+ fibronectin splicing variant is overexpressed in psoriatic non-lesional epidermis and sensitizes keratinocytes to mitogenic signals. However, regulation of its abundance is only partially understood. In our recent cDNA microarray experiment, we identified three SR-rich splicing factors-splicing factor, arginine/serine-rich 18 (SFRS18), peptidyl-prolyl cis-trans isomerase G (PPIG), and luc-7 like protein 3 (LUC7L3)-which might be implicated in the preactivated states of keratinocytes in psoriatic non-involved skin and could also contribute to the regulation of fibronectin mRNA maturation. In this study, we investigated the role of LUC7L3, PPIG, and SFRS18 in psoriasis and in the mRNA maturation process of fibronectin. Regarding tissue staining experiments, we were able to demonstrate a characteristic distribution of the splicing factors in healthy, psoriatic non-involved and involved epidermis. Moreover, the expression profiles of these SR-rich proteins were found to be very similar in synchronized keratinocytes. Contribution of splicing facwwtors to the EDA+ fibronectin formation was also confirmed: their siRNA silencing leads to altered fibronectin mRNA and protein expression patterns, suggesting the participation in the EDA domain inclusion. Our results indicate that LUC7L3, PPIG, and SFRS18 are not only implicated in EDA+ fibronectin formation, but also that they could possess multiple roles in psoriasis-associated molecular abnormalities.
Subject(s)
Fibronectins/biosynthesis , Keratinocytes/metabolism , Psoriasis/metabolism , RNA Splicing Factors/biosynthesis , RNA Splicing , RNA, Messenger/metabolism , Adolescent , Adult , Cyclophilins/biosynthesis , Female , Humans , Keratinocytes/pathology , Male , Middle Aged , Nuclear Proteins , Psoriasis/pathology , RNA-Binding Proteins/biosynthesisABSTRACT
Sharing rides could drastically improve the efficiency of car and taxi transportation. Unleashing such potential, however, requires understanding how urban parameters affect the fraction of individual trips that can be shared, a quantity that we call shareability. Using data on millions of taxi trips in New York City, San Francisco, Singapore, and Vienna, we compute the shareability curves for each city, and find that a natural rescaling collapses them onto a single, universal curve. We explain this scaling law theoretically with a simple model that predicts the potential for ride sharing in any city, using a few basic urban quantities and no adjustable parameters. Accurate extrapolations of this type will help planners, transportation companies, and society at large to shape a sustainable path for urban growth.
ABSTRACT
We have previously demonstrated that the E3 ligase Human Constitutive Photomorphogenic Protein (huCOP1) is expressed in human keratinocytes and negatively regulates p53. The MutS homolog 2 (MSH2) protein plays a central role in DNA MMR mechanism and is implicated in the cellular response to anticancer agents, such as cisplatin. Our aim was to clarify whether huCOP1 plays a role in DNA MMR by affecting MSH2 protein level in human keratinocytes. To define the role of huCOP1 in DNA mismatch repair, we determined whether huCOP1 affects MSH2 abundance. MSH2 protein level was detected by immunocytochemical staining using a keratinocyte cell line in which the expression level of huCOP1 was stably decreased (siCOP1). To investigate whether huCOP1 silencing influences cisplatin-induced cell death, control and siCOP1 keratinocyte cells were treated with increasing concentrations of cisplatin and cell viability was recorded after 48 and 96 h. Stable silencing of huCOP1 in human keratinocytes resulted in a reduced level of MSH2 protein. huCOP1 silencing also sensitized keratinocytes to the interstrand crosslinking inducer cisplatin. Our results indicate that decreased huCOP1 correlates with lower MSH2 levels. These protein level changes lead to increased sensitivity toward cisplatin treatment, implicating that huCOP1 plays a positive role in maintaining genome integrity in human keratinocytes.
Subject(s)
DNA Repair , Genomic Instability/physiology , Keratinocytes/metabolism , Ubiquitin-Protein Ligases/metabolism , Cell Line, Transformed , Cisplatin/pharmacology , Genomic Instability/drug effects , Humans , MutS Homolog 2 Protein/metabolism , Tumor Suppressor Protein p53/metabolismABSTRACT
BACKGROUND: Papillon-Lefévre syndrome (PLS; OMIM 245000) and Haim-Munk syndromes (HMS; OMIM 245010) are phenotypic variants of the same rare disease caused by mutations of the cathepsin C (CTSC) gene, and they exhibit autosomal recessive inheritance. AIMS: To identify diseases caused by mutations of the CTSC gene in two Hungarian patients and to perform haplotype analysis to elucidate any familial relationship between them. METHODS: Mutation screening and polymorphism analysis were performed by direct sequencing of the CTSC gene. RESULTS: Mutation screening of the CTSC gene from the two patients revealed the presence of the same homozygous nonsense mutation (c.748C/T; p.Arg250X). However, one patient exhibited the PLS phenotype and the other the HMS phenotype. Although these patients were not aware that they were related, haplotype analysis, especially the genotypes of the rs217116 and the rs217115 polymorphisms, clearly indicated that the patients carry the same haplotype, whereas the unrelated healthy controls carried several different haplotypes. CONCLUSIONS: Our results demonstrate that PLS and HMS are phenotypic variants of the same disease and, additionally, exclude the presence of a putative genetic modifier factor within the CTSC gene that is responsible for the development of the two phenotypes. We suggest that this putative genetic modifier factor is located outside the CTSC gene, or alternatively, that the development of the different phenotypes is the consequence of different environmental or lifestyle factors.
Subject(s)
Acro-Osteolysis/genetics , Cathepsin C/genetics , Codon, Nonsense , Papillon-Lefevre Disease/genetics , Adult , Female , Genotype , Humans , Male , PhenotypeABSTRACT
BACKGROUND: Data indicate that in psoriasis, abnormalities are already present in nonlesional skin. Transforming growth factor-ß and keratinocyte growth factor (KGF), together with fibronectin and α5ß1 integrin, were suggested to play a crucial role in the pathogenesis of psoriasis by influencing inflammation and keratinocyte hyperproliferation. OBJECTIVES: To investigate the expression of KGF, fibroblast growth factor receptor (FGFR)2, fibronectin (FN) and extra domain A (EDA)-positive FN in healthy and nonlesional psoriatic skin, and to study the effect of KGF on the regulation of FN and EDA(+) FN production by fibroblasts. METHODS: Healthy, nonlesional psoriatic skin and lesional psoriatic skin were immunostained for α5 integrin, KGF, FGFR2, EDA(+) FN and signal transducer and activator of transcription (STAT)1. KGF-treated cell cultures were analysed for FN and EDA(+) FN mRNA and protein by real-time reverse-transcriptase polymerase chain reaction and flow cytometry, respectively. The major downstream signalling of KGF was investigated by blocking experiments using inhibitors of mitogen-activated protein kinase (MAPK) kinase (MEK1), AKT1/2, STAT1 and STAT3. RESULTS: The expression of α5 integrin, EDA(+) FN, KGF and its receptor FGFR2 is elevated in psoriatic nonlesional skin compared with healthy skin. KGF mildly induced EDA(+) FN, but not FN expression in healthy fibroblasts through MAPK signalling. Fibroblasts express the FGFR2-IIIc splice variant. STAT1 negatively regulates both FN and EDA(+) FN expression in healthy fibroblasts, and this regulation is compromised in fibroblasts derived from nonlesional psoriatic dermis. We detected active STAT1 in healthy and lesional skin, similarly to a previous report. However, in the nonlesional skin STAT1 activation was absent in tissues far away from lesions. CONCLUSIONS: The production of FN and EDA(+) FN by fibroblasts and the signalling of STAT1 are abnormally regulated in psoriatic nonlesional skin.
Subject(s)
Fibroblast Growth Factor 7/physiology , Fibroblasts/metabolism , Fibronectins/biosynthesis , Psoriasis/metabolism , Adolescent , Adult , Case-Control Studies , Cells, Cultured , Fibronectins/metabolism , Healthy Volunteers , Humans , Keratinocytes/metabolism , MAP Kinase Signaling System/physiology , Melanocytes/metabolism , Middle Aged , Receptor, Fibroblast Growth Factor, Type 2/biosynthesis , Receptor, Fibroblast Growth Factor, Type 2/metabolism , STAT1 Transcription Factor/metabolism , STAT3 Transcription Factor , Transforming Growth Factor beta/biosynthesis , Transforming Growth Factor beta/metabolism , Young AdultABSTRACT
BACKGROUND: Langerhans cell histiocytosis (LCH) is characterized by the proliferation of pathologic Langerhans cells. The disease can develop in any age and can affect almost any organ. Cutaneous involvement is frequent in LCH. The recent demonstration of the activating, oncogenic BRAFV600E gene mutation in LCH samples strongly supports the neoplastic origin of the disease. OBJECTIVES: Our aim was to analyse the clinical data of the patients and whether BRAFV600E mutation is present in skin lesions of patients with adult onset LCH, and to investigate whether the BRAFV600E mutation status has any effect on the clinical presentation and the outcome of the disease. METHODS: We diagnosed and treated 15 adult LCH patients in the period of 1987-2012 and collected their clinical data. Three of our patients suffered from skin involvement and 12 patients had multiorgan disease (five patients out of the multisystem group died). Eleven formalin-fixed paraffin-embedded skin samples from 10 patients were available for BRAFV600E mutation analysis. RESULTS: Among the 11 examined samples, 6 contained the BRAFV600E mutation (54.5%). Our results indicate that in the adult group of LCH patients the presence of BRAFV600E mutation is similar to what was previously suggested in case of the childhood forms, at least as far as skin lesions are concerned. The BRAF mutation status of our patients does not seem to correlate with the extent and/or the outcome of the disease. CONCLUSION: Our results support the neoplastic origin of LCH and suggest that skin lesions of LCH are sufficient for the diagnosis of the disease and for assessing its BRAF status. In addition, analysis of BRAF status of patients with LCH can lead to the administration of new targeted therapies which may provide better disease control and prognosis.
Subject(s)
Histiocytosis, Langerhans-Cell/genetics , Histiocytosis, Langerhans-Cell/pathology , Proto-Oncogene Proteins B-raf/genetics , Skin Diseases/genetics , Skin Diseases/pathology , Adult , Age of Onset , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Mutation , Severity of Illness Index , Young AdultABSTRACT
Ultraviolet (UV) B is the most prominent physical carcinogen in the environment leading to the development of various skin cancers. We have previously demonstrated that the human ortholog of the Arabidopsis thaliana constitutive photomorphogenesis 1 (COP1) protein, huCOP1, is expressed in keratinocytes in a UVB-regulated manner and is a negative regulator of p53 as a posttranslational modifier. However, it was not known whether huCOP1 plays a role in mediating the UVB-induced early transcriptional responses of human keratinocytes. In this study, we report that stable siRNA-mediated silencing of huCOP1 affects the UVB response of several genes within 2 h of irradiation, indicating that altered huCOP1 expression sensitizes the cells toward UVB. Pathway analysis identified a molecular network in which 13 of the 30 examined UVB-regulated genes were organized around three central proteins. Since the expression of the investigated genes was upregulated by UVB in the siCOP1 cell line, we hypothesize that huCOP1 is a repressor of the identified pathway. Several members of the network have been implicated previously in the pathogenesis of non-melanoma skin cancers; therefore, clarifying the role of huCOP1 in these skin diseases may have clinical relevance in the future.
Subject(s)
Gene Expression Regulation/radiation effects , Keratinocytes/metabolism , Keratinocytes/radiation effects , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism , Ultraviolet Rays/adverse effects , Cell Line , Gene Regulatory Networks/radiation effects , Gene Silencing , Humans , RNA, Small Interfering/genetics , Time Factors , Transcription, Genetic/radiation effects , Ubiquitin-Protein Ligases/deficiencyABSTRACT
OBJECTIVE: In polycythaemia vera (PV) and essential thrombocythaemia (ET), the life expectancy of the patients is greatly affected by thrombotic events. An investigation was performed of the potential association of PV/ET, and thrombotic complications with cardiovascular (CV) risk factors, a leukocyte count at the haematological diagnosis > 11.1 G/L, and the JAK2V617F mutation. PATIENTS AND METHODS: In the period 1998-2011, 128 women with a median age of 62 years were enrolled. RESULTS: The risk of thrombotic events before the diagnosis was 32.8% (42/128), while in the follow-up period it was 10.2% (13/128). The difference in the probability of thrombosis-free survival between those with at most one CV risk factor and those with two or more CV risk factors was significant (p = 0.005). The presence of two or more CV risk factors (univariate: p = 0.011; multivariate: relative risk: 4.728, 95% CI 1.312-17.040; p = 0.018) significantly increased the risk of thrombosis. Univariate analyses revealed that high blood pressure (p = 0.001), hyperlipidaemia (p = 0.005) and cigarette smoking (p = 0.051) were associated with a significantly higher risk of thrombosis. Analyses of the influence of the leukocyte count (univariate: p = 0.424; multivariate: relative risk: 1.407, 95% CI 0.359-5.507; p = 0.624) and the JAK2V617F mutation (univariate: p = 0.367; multivariate: relative risk: 1.428, 95% CI 0.316-6.460; p = 0.643) on subsequent thrombotic complications resulted in a non-signicant tendency. CONCLUSIONS: Female patients who display CV risk factors (high blood pressure, hyperlipidaemia and/or cigarette smoking) and PV or ET may well be at a higher risk of thrombotic events and require special consideration as concerns as the prevention and management of thrombotic events.
Subject(s)
Polycythemia Vera/epidemiology , Thrombocythemia, Essential/epidemiology , Thrombophilia/epidemiology , Thrombosis/epidemiology , Adolescent , Adult , Aged , Aged, 80 and over , Chronic Disease , Female , Follow-Up Studies , Humans , Hypertension/blood , Hypertension/diagnosis , Hypertension/epidemiology , Middle Aged , Myeloproliferative Disorders/blood , Myeloproliferative Disorders/diagnosis , Myeloproliferative Disorders/epidemiology , Polycythemia Vera/blood , Polycythemia Vera/diagnosis , Risk Factors , Smoking/adverse effects , Smoking/epidemiology , Thrombocythemia, Essential/blood , Thrombocythemia, Essential/diagnosis , Thrombophilia/blood , Thrombophilia/diagnosis , Thrombosis/blood , Thrombosis/diagnosis , Young AdultABSTRACT
BACKGROUND: Acne vulgaris is a common and clinically well-characterized skin disease that affects a great proportion of the general population and thus, is a major public health problem. The aim of the present study was to investigate whether TNFA -308 G > A polymorphism might be involved in the pathogenesis of acne in a population from Sicily. METHODS: A total of 74 patients with acne and of 88 healthy control subjects from Catania, Italy were examined in the present study. TNFA -308 G > A polymorphisms using the PCR-RFLP method were determined in DNA extracted from buccal swabs. RESULTS: When controls were compared to acne patients, their genotype distributions, respectively G/G: 64.3%, G/A: 35.7% and G/G: 74.0%, G/A: 26.0%, were shown to be different, although not statistically significant (p = 0.191). A significant protective association between the TNFA -308 GA genotype and acne in males (p = 0.027; OR95% CI: 0.288; 0.094-0.889) was shown. CONCLUSIONS: The present results suggest that TNFA -308 polymorphism may contribute to acne susceptibility, as suggested by the protective effect of the G/A phenotype in the males of the Sicilian cohort. Further studies in larger groups, investigating the TNFA -308G/A or other polymorphisms of this gene in acne patients may be helpful to clarify the pathogenesis of the disease.
Subject(s)
Acne Vulgaris/genetics , Genetic Predisposition to Disease , Polymorphism, Genetic , Tumor Necrosis Factor-alpha/genetics , Adult , Female , Humans , Male , Middle Aged , Sicily , Young AdultABSTRACT
BACKGROUND: The major locus for melanoma predisposition is the cell cycle regulatory CDKN2A gene on chromosome 9p21. However, the frequency of germline coding mutations of the CDKN2A gene is lower than expected in melanoma-prone families linked to chromosome 9p21. OBJECTIVES: To investigate whether the rare IVS1+37 G/C intronic mutation of the CDKN2A gene, recently identified in a Hungarian melanoma-prone family, influences mRNA splicing regulation. METHODS: CDKN2A minigenes containing the wild-type and the mutant intronic sequence were created and transfected into HeLa cells with the aim of studying the mRNA transcripts. RESULTS: The results revealed the emergence of a differential splicing pattern from the wild-type and the mutant minigene, suggesting that this mutation may alter the splicing of CDKN2A primary mRNA and therefore might have a pathogenetic role in familial melanoma. CONCLUSIONS: We believe that these results confirm the importance of the identification and characterization of CDKN2A intronic mutations with a view to improving our understanding of the pathogenesis, and explain why the frequency of germline coding mutations of the CDKN2A gene is lower than expected in melanoma-prone families linked to chromosome 9p21.
Subject(s)
Chromosomes, Human, Pair 9/genetics , Genes, p16/physiology , Germ-Line Mutation/genetics , Introns/genetics , Melanoma/genetics , Skin Neoplasms/genetics , Cyclin-Dependent Kinase Inhibitor p16/genetics , Female , Genetic Predisposition to Disease/genetics , Humans , Male , Pedigree , RNA Splicing/geneticsABSTRACT
Acne vulgaris is a common chronic inflammatory skin disease of multifactorial origin. The aim of this study was to clarify whether known polymorphisms of the interleukin-1A (IL1A) and IL1RN genes play a role in the pathogenesis of acne vulgaris. A positive association was found between the minor T allele of the IL1A +4845(G>T) single nucleotide polymorphism (SNP) and acne, whereas no association was found with respect to any alleles of the variable number of tandem repeats (VNTR) polymorphism of the IL1RN gene. The severity of inflammatory acne symptoms correlated with the percentage of individuals carrying the homozygote T/T genotype. These results may help to elucidate the molecular events leading to the development of acne.
Subject(s)
Acne Vulgaris/genetics , Acne Vulgaris/immunology , Interleukin-1alpha/genetics , Polymorphism, Single Nucleotide , Alleles , Case-Control Studies , Female , Gene Frequency , Genetic Predisposition to Disease , Humans , Interleukin 1 Receptor Antagonist Protein/genetics , Male , Minisatellite Repeats , Retrospective StudiesABSTRACT
The aim of our study was to investigate the incidence of duodeno-gastroesophageal reflux-induced malignant transformation in a series of duodeno-esophageal anastomosis operations in rats. This surgical method provides a model for reflux-induced esophageal pathologies, without carcinogen administration. The study design included the follow-up of 31 cases. Thirty weeks of duodeno-gastroesophageal reflux disease significantly increased the risk of the development of Barrett's esophagus, and reflux-induced esophageal adenocarcinoma formation was evident in four animals. In one of these particular cases, a superficial squamous cell cancer was noted in close vicinity to the adenocarcinoma formation. For further analysis, a detailed immunohistochemical staining protocol was used. The immunophenotypes revealed cyclin D1 expression (nuclear positivity in 35% of all the squamous cells), p53 protein accumulation (50% nuclear positivity), with a low expression of cox-2, and negative c-erbB2 staining in the squamous carcinoma cells. The specialized intestinal metaplasia and mucinous adenocarcinoma cells exhibited exclusively diffuse cox-2 positivity (90% of all glandular cells) and weak focal c-erbB2 (5%) staining, without cyclin D1 expression or p53 protein accumulation. Real-time polymerase chain reaction was applied to quantify the abundance of p53, cyclin D1 and cox-2 mRNAs in this biopsy. The most dramatic changes were observed in the level of expression of cyclin D1 (a 9.08-fold expression as compared with the non-treated esophagus samples), while the p53 and cox-2 gene expressions were increased by 1.61 and 2.45-fold, respectively, relative to the non-treated samples. The results afford evidence of the simultaneous activation of more than one possible carcinogenetic pathway in experimental gastroesophageal reflux disease. Synchronous neoplasm formation with different growth pattern characteristics is a rarity in humans, and this phenomenon suggests that the presented model is a suitable means of mimicking the whole spectrum of human gastroesophageal reflux disease pathology.
Subject(s)
Adenocarcinoma/genetics , Carcinoma, Squamous Cell/genetics , Gastroesophageal Reflux/complications , Animals , Chronic Disease , Disease Models, Animal , Male , Phenotype , Rats , Rats, Sprague-DawleyABSTRACT
Dengue is the most important human viral disease transmitted by an arthropod vector. The steadily increasing numbers of tourists visiting endemic areas coupled with the present resurgence of dengue, raises the risk of exposure for large numbers of travelers and imported dengue cases are increasingly observed in non-endemic countries. We aimed to study the epidemiology, clinical manifestations and laboratory findings in imported dengue at a City of Vienna hospital. Medical records of 93 patients (age: 17-68 years, 43f, 50m) with imported dengue in Vienna between 1990 and April 2005 were analyzed retrospectively. Forty-eight (52%) were classified as confirmed and 45 (48%) as probable dengue, according to the CDC criteria. The patients acquired the infection in South East Asia (56%), the Indian subcontinent (18%), Africa (10%) and Oceania (3%). The most important symptoms were fever, headache, arthralgia and myalgia, nausea and vomiting, diarrhea, chills, extreme fatigue and dizziness. A rash was observed in 43%, and lymphadenopathy in 22%. Laboratory findings were thrombocytopenia, leukopenia and elevated hepatic enzymes. Eighteen patients showed hemorrhagic manifestations, and 7 fulfilled the criteria of dengue hemorrhagic fever; 1 of them had dengue shock syndrome. Case fatality rate was nil. Dengue has to be considered in all febrile travelers returning from endemic areas. Prompt diagnosis and symptomatic treatment is warranted and should prevent patients from unnecessary and potentially harmful diagnostic and therapeutic procedures.
Subject(s)
Dengue/epidemiology , Travel , Adolescent , Adult , Aedes , Aged , Animals , Austria/epidemiology , Dengue/blood , Dengue/transmission , Female , Humans , Insect Vectors , Male , Middle Aged , Retrospective Studies , Serologic TestsABSTRACT
The failure rate of primary empirical anti-infective treatment of community-acquired pneumonia is reported to range between 2 and 7%. These patients are subject to a greater risk of intensive medical treatment and a higher mortality rate than patients who respond to primary treatment. We investigated 63 patients in a "real life scenario" who were admitted to the hospital after failure of primary outpatient therapy for community-acquired pneumonia. Thirty-three patients received intravenous standard therapy (betalactam 14, macrolide 3, levofloxacin 6, doxycycline 1, combinations 9 patients) while 30 patients were treated with intravenous moxifloxacin. The oral antibiotic pretreatment that failed most frequently was clarithromycin (n = 25), followed by amoxicillin/clavulanic acid (n = 16), cefixime (n = 10), cefuroxime/axetil (n = 5), doxycycline (3), cefpodoxime, and ciprofloxacin (2 each). There were no differences between the two groups in respect of age, gender, numbers of patients in nursing homes, numbers of patients with different underlying diseases (chronic bronchitis, coronary heart disease, diabetes mellitus, smoking, etc.), severity of pneumonia at the time of admission, numbers of patients requiring intensive care, and lethality. The group that underwent standard therapy experienced failure of the empirical intra-hospital antibiotic therapy more often during therapy [10 (30%) patients vs 2 (6%) in the moxifloxacin group, p = 0.009] and clinical failure of treatment on day 28 after initiation of therapy [7 (21%) patients vs 2 (6%) in the moxifloxacin group, p = 0.003]. In cases of failure of empirical preclinical antibiotic treatment for community-acquired pneumonia, subsequent intrahospital treatment with moxifloxacin is more successful than standard therapy in our study reflecting a "real life scenario".
Subject(s)
Anti-Bacterial Agents/therapeutic use , Aza Compounds/therapeutic use , Pneumonia, Bacterial/drug therapy , Quinolines/therapeutic use , Adult , Aged , Aged, 80 and over , Doxycycline/therapeutic use , Drug Therapy, Combination , Female , Fluoroquinolones , Hospitalization , Humans , Levofloxacin , Macrolides/therapeutic use , Male , Middle Aged , Moxifloxacin , Ofloxacin/therapeutic use , Treatment Failure , beta-Lactams/therapeutic useABSTRACT
Perioperative antibiotic prophylaxis in orthopaedics is only indicated if a foreign body such as a prosthetic joint remains in the operation site. For this indication first or second generation cephalosporins should be preferred. It is essential to administer the antibiotic within 30 min before incision. In the case of an extended intervention (more than 3 h) a repeated dose should be considered. It is evidence-based that prolonged perioperative antibiotic prophylaxis (more then 24 h) is not beneficial. To avoid the emergence of resistances or hygienic insufficiencies surveillance of surgical site infections should be enforced. Optimal conditions are necessary to achieve a rate of surgical site infection in orthopaedics below 1% in patients with normal infection risk profile.