SERPINA1 Gene Variants in Granulomatosis with Polyangiitis.

Alpha-1 antitrypsin (A1AT) deficiency is one of the most common genetic disorders in Caucasian population. There is a link between granulomatosis with polyangiitis (GPA) and most frequent variants of SERPINA1 gene encoding severe alpha-1 antitripsin deficiency. However, the potential effect of Pi*Z, Pi*S as well as other SERPINA1 variants on clinical course of vasculitis are not well understood. The aim of the study was to analyze the potential effect of A1AT protein phenotype representing the SERPINA1 gene variants on the clinical course of GPA. The study group consisted of 64 subjects with GPA, stratified according to the disease severity: patients in active phase (group I, n = 12), patients during remission on treatment (group II, n = 40) or untreated (group III, n = 12). Normal Pi*MM SERPINA1 genotype was detected by means of real-time polymerase chain reaction (PCR) or direct sequencing in 59 patients, Pi*MZ genotype in 2, and Pi*IM, Pi*MS or Pi*SZ in 1 patient respectively. The patients with abnormal Pi*Z, Pi*S, or Pi*I allele constituted 17% in group I, 5% in group II, and 8% in group III. The serum content of A1AT and high sensitivity C-reactive protein (hsCRP) assessed by nephelometry did not differ between the groups. Interestingly, the mean serum antiPR3-antibodies level detected by Elisa method was significantly greater in the GPA patients with Pi*Z, Pi*S, or Pi*I SERPINA1 variants than in the Pi*MM homozygotes. In summary, heterozygous Pi*MZ, Pi*MS, and Pi*SZ genotype was detected in 7.8% of total group of GPA patients, and in 10.5% of those with lung lesions. The abnormal alleles of Pi*S and Pi*Z may affect the clinical course of the disease.

Clinical Manifestations of Huge Diaphragmatic Hernias.

Translocation of abdominal organs into the thoracic cavity may cause dyspnea, heart disorders, and gastric symptoms. Diaphragmatic hernias can cause diagnostic difficulties, since both clinical and radiological symptoms might imitate different disorders. In these cases computed tomography of the chest is the method of choice. The aim of this study was to assess clinical manifestations, risk factors, and prognosis in patients with huge diaphragmatic hernias with displacement of abdominal organs into the thorax, depending on the action taken. We carried out a retrospective study using data of patients hospitalized in the years 2012-2016. Ten patients were qualified for the study (8 women and 2 men). The mean age of the subjects was 86.5 ± 10.5 years. Thirty percent of the hernias were post-traumatic. All of the patients reported cardiovascular or respiratory symptoms. Upper gastrointestinal symptoms occurred in half of the patients. Twenty percent of patients underwent surgery with a positive outcome, while 30% of patients, who were not qualified for surgery due to numerous co-morbidities, died. The main risk factors predisposing to the occurrence of large diaphragmatic hernias were the following: old age, female gender, and thoracic cage deformities.

Lung Lesions During Fever of Unknown Origin.

Fever of unknown origin (FUO) remains one of the most difficult diagnostic challenges. The causes of FUO can be various diseases located in different organs. The aim of the study was to determine the prevalence and nature of pulmonary lesions during FUO. One hundred and sixty one patients with FUO participated in this prospective study. We performed a detailed comprehensive history, physical examination, and a wide spectrum of tests. The most common causes of FUO were infections (39%), autoimmune conditions (28%), and neoplasms (17%). Lung lesions were found in 30% of patients. In this group 35% were infections, 30% autoimmune diseases, and 4% cancer. Among patients with respiratory infections, there were cases of tuberculosis, atypical pneumonia, lung abscess, and bronchiectases. Autoimmune pulmonary lesions were observed during vasculitis and systemic lupus. The causes of FUO in the group of patients with lung lesions were also pulmonary embolism, sarcoidosis, and pulmonary fibrosis. Chest CT played an important role in the diagnosis of the causes of FUO with pulmonary manifestations. Pulmonary lesions are a common cause of FUO. Most FUO with pulmonary lesions are recognized during infections and autoimmune diseases. An important part of diagnosing FUO is a detailed evaluation of the respiratory system.

Echocardiographic Assessment in Patients with Granulomatosis with Polyangiitis.

Granulomatosis with polyangiitis (GPA) is one of the most common forms of systemic vasculitis, which usually involves the upper and lower respiratory tract, but it may affect also multiple organs. The aim of the study was an echocardiographic evaluation of cardiac involvement in GPA patients during remission. Eighty eight patients with GPA were evaluated in the study. The control group consisted of 40 age and sex-matched patients without a previous history of cardiovascular disease. We found that there were no differences between GPA and control groups regarding left atrial enlargement and interventricular septal hypertrophy. In one GPA patient, all heart chambers were enlarged. Left ventricle systolic function was decreased (LVEF ≤ 50%) in eight patients with GPA, and left ventricle wall motion abnormalities were observed in 12 patients. Left ventricle relaxation dysfunction, mitral valve and tricuspid valve regurgitation were observed with the same frequency in both GPA and control groups. Aortic regurgitation was the single abnormality that occurred significantly more often in the GPA group than in controls (28% vs. 7.5%; p = 0.03). Pericardial effusion was observed in three GPA patients and in none from the control group. We conclude that the most common echocardiographic manifestation in GPA patients in remission was aortic valve regurgitation. However, cardiac involvement in such patients is rather rare and in the majority of cases clinically insignificant.

Microbiological spectrum and susceptibility pattern of clinical isolates from the neonatal unit in a single medical center.

BACKGROUND: Infections are a frequent and significant cause of morbidity and mortality in neonatal units. The bacterial pathogens and their susceptibility patterns should be monitored in hospital settings. The aim of the study was to describe the distribution of the bacterial agents and their antibiotic resistant and susceptibility patterns in the Special Neonatal Care Unit (SNCU). MATERIAL AND METHODS: A retrospective analysis of results of microbiologically tested samples (blood, cerebrospinal fluid, urine, stool, eye excretions, external ear swabs, nasopharyngeal swabs and skin swabs) taken from newborns hospitalized in one SNCU in Warsaw (Poland) was conducted. The period analyzed was from July 1st, 2010 to December 31st, 2010. RESULTS: A total of 838 cultured samples were collected in the period analyzed. Three hundred seventy three of them (44.5%) were positive. The majority of the cultured microorganisms were classified as colonization: 338/373 (91%) strains. Gram negative bacteria were predominant colonizing flora: 227/338 (67%) strains. Gram positive bacteria were predominant causative agents in newborns with infections: 26/35 (74%) strains. 57.9% of Escherichia coli isolates were resistant to amoxicillin and ampicillin. 100% of Klebsiella pneumoniae were resistant to amikacin and netilmicin. Staphylococcus aureus methicillin resistant strains were cultured in 2.7% of cases. CONCLUSIONS: Gram negative species continue to be predominant agents of neonatal colonizing flora while gram positive bacteria remain important causative agents for symptomatic infections. Continuous monitoring of bacterial flora and its antibiotic susceptibility pattern is necessary to provide a successful antibiotic policy. Current results may be used for future national and international comparison.

Epidemiological and clinical reasons for vaccination against pertussis and influenza in pregnant women.

Vaccinations in pregnancy are an important aspect of prenatal care for improving both maternal health and neonatal outcomes. Despite the fact that protection against some infectious diseases for pregnant women can be easily provided through immunizations, current coverage rates are low. Two vaccines are notably recommended during pregnancy: influenza and the combined tetanus, diphtheria and acellular pertussis (Tdap) vaccine. In this review the authors discuss current recommendations for vaccination against pertussis and influenza in pregnant women in terms of epidemiological, clinical, and immunological reasons, taking into account safety and effectiveness. Promoting patients' awareness about pertussis and influenza and encouraging general practitioners, nurses and obstetricians to recommend the pertussis booster and influenza vaccine will hopefully increase the number of pregnant women who choose to become vaccinated.

Etiology and complications of central nervous system infections in children treated in a pediatric intensive care unit in Poland.

Central nervous system infections are significant causes of mortality and long-term neurologic complications in children. Survivors often require an extended period of rehabilitation. The authors carried out a retrospective analysis of 1158 children (aged 1 month to 16 years; 31 boys) treated in one pediatric intensive care unit in Warsaw between 2002 and 2010. Forty-three of 1158 (3.7%) children presented with neuroinfections. Nearly two-thirds of the children were younger than age 5 years. The majority of cases (62.8%) were vaccine-preventable bacterial infections. The most frequent complications were brain edema (30.2%), brain hemorrhage (27.9%), and secondary nosocomial pneumonia (25.6%). One-fifth of children developed late, long-term neurologic complications. The mortality rate was 20.9%. The study showed that central nervous system infections are significant causes of hospitalization in the pediatric intensive care unit and often result in death or long-term complications. These infections mainly affect children younger than age 5 years. The majority could be prevented with immunizations.

Accuracy of rapid influenza detection test in diagnosis of influenza A and B viruses in children less than 59 months old.

Influenza burden among children is underestimated. Rapid influenza diagnostic tests (RIDTs) may be helpful in the early diagnosis of the disease, but their results should be interpreted cautiously. The aim of our study was to estimate the accuracy of the rapid influenza detection test BD Directigen™ EZ Flu A+B (Becton, Dickinson and Company, Sparks, MD) used among children with influenza-like illness (ILI) consulted in the ambulatory care clinics. A total number of 150 patients were enrolled into the study. The inclusion criteria were: age of the child less than 59 months, presentation of ILI according to CDC definition (fever >37.8 °C, cough, and/or sore throat in the absence of another known cause of illness), and duration of symptoms shorter than 96 h. In all patients two nasal and one pharyngeal swab were obtained and tested by RIDT, RT-PCR, and real time RT-PCR. For or influenza A(H1N1)pdm09, virus sensitivity of RIDT was 62.2 % (95 %CI 53.4-66.5 %), specificity 97.1 % (95 %CI 93.4-99 %), positive predictive value (PPV) 90.3 % (95 %CI 77.5-96.5 %), and negative predictive value (NPV) 85.7 % (95 %CI 82.4-87.3 %). For influenza B, virus sensitivity was 36.8 % (95 %CI 23.3-41.1 %), specificity 99.2 % (95 %CI 97.3-99.9 %), PPV 87.5 % (95 %CI 55.4-97.7 %), and NPV 91.5 % (95 % CI 89.7-92.1 %). We conclude that the RIDT immunoassay is a specific, but moderately sensitive, method in the diagnosis of influenza type A and is of low sensitivity in the diagnosis of influenza B infections in infants and children.

Clinical features and outcomes of influenza A and B infections in children.

The aim of the study was to describe the course of influenza among children aged 0-59 months. A total of 150 children with influenza-like symptoms (ILI): cough, fever >37.8 °C, and sore throat was included into the observation. All children were tested with both rapid influenza detection test (RIDT) BD Directigen™ EZ Flu A+B® and RT-PCR. Sixty four cases of influenza were diagnosed (incidence rate 40 %): 19 (30 %) cases of influenza caused by type B virus and 45 (70 %) cases caused by type A virus. Children with influenza required more often follow up visits (p < 0.05, OR 1.99, 95 % CI 1.03-3.85) and less often were administrated antibiotic therapy (p < 0.05, OR 0.25, 95 % CI 0.04-0.97). The logistic regression analysis revealed that only positive result of rapid influenza detection test, not any of clinical symptoms, could be found as an independent predictor of influenza (OR 4.37, 95 % CI 2.03-9.43). Patients with influenza type A more often reported muscle ache (p < 0.05) and complications (p < 0.05; OR 6.06, 95 % CI 1.20-60.38). Otitis media occurred more often among patients with than without influenza (p < 0.01; OR 15.50, 95 % CI 2.10-688.5). We conclude that although influenza infections among children younger than 59 months were generally mild and self-limited, pediatric burden of the disease was significant.

Immunization coverage against capsular bacteria in splenectomized patients.

Splenectomy significantly increases the risk of severe invasive infections caused by capsular bacteria, such as sepsis and meningitis. Immunizations before and after splenectomy reduce the risk and are routinely recommended. Little is known about compliance with actual immunization guidelines in Poland. The aim of this study was to analyze the vaccination rate and the knowledge of splenectomized patients concerning immunizations in Poland. We applied a questionnaire to survey 85 adult patients (F/M 49/36) splenectomized in 2009-2010 and analyzed the patients' medical files and immunization certificates. Patients were also questioned over the phone. We found that the patients were most commonly immunized against Streptococcus pneumoniae (17/85, 20 %), less often against Haemophilus influenzae b (8/85, 9.4 %), and rarely against Niesseria meningitidis C (3/85, 3.5 %). In contrast, hepatitis B immunization coverage rate was as high as 67 % (57/85). The majority of respondents (59/85, 69.4 %) regarded information about the recommended immunizations as insufficient and rated their doctor's reasoning as inconsistent, a smaller number (20/85, 23.5 %) confirmed they received sound information before splenectomy. Both surgeons and primary care physicians did not offer immunizations to the majority of patients (59/85, 69.4 %); as a result, only 30.6 % of patients (26/85) were immunized against any capsular bacteria before splenectomy. In conclusion, the majority of splenectomized patients are not immunized despite current guidelines and do show an inadequate level of knowledge concerning the consequences of splenectomy. It is important that both surgeons and primary care doctors give patients clear instructions about immunizations and antibiotics recommended before and after their splenectomy.

Cancer incidence in pulmonary vasculitis.

Pulmonary vasculitis is a potentially lethal autoimmune disease characterized by granulomatous inflammation of respiratory tract, necrotizing vasculitis affecting small-to medium-size vessels and antineutrophil cytoplasmic antibodies elevation. Typical therapy involves high-dose glucocorticosteroids combined with cyclophosphamide in a dose 1-2 mg/kg/per day. A high relapse rate in pulmonary vasculitis means prolonged courses of cyclophosphamide in some patients. Carcinogenic effects of cyclophosphamide, especially its toxic metabolite acrolein that is excreted into the urine, are responsible for the development of acute myeloid leukemia (AML) and bladder cancer. These and other malignancies are cyclophosphamide dose-depended. The aim of the present study was to assess the incidence of cancer in patients with pulmonary vasculitis in comparison with the incidence of cancer in the general population. Analyses were done according to the cumulative dose of cyclophosphamide, subdivided into low (≤35 g) and high (>35 g). During the observation period 15 cancers occurred. A significantly increased standardized incidence ratio (SIR) was observed for non-melanoma skin cancers (SIR 5.2; 95 % Cl 2.3-8.7), AML (SIR 4.3; 95 % Cl 2.1-11.2), and bladder cancer (SIR 3.4; 95 % Cl 1.6-5.2). Induction remission treatment and relapse treatment with cyclophosphamide involves a substantial risk of late appearing malignances in patients with pulmonary vasculitis. Monitoring and prophylactic management in pulmonary vasculitis after cessation of cyclophosphamide therapy is crucial.

Nosocomial rotavirus gastroenterocolitis in a large tertiary paediatric hospital in Warsaw, 2006-2010.

INTRODUCTION: Rotaviruses are the leading cause of community-acquired and nosocomial gastroenterocolitis in children. There are limited data concerning the epidemiology of nosocomial rotavirus gastroenterocolitis (NRVG) in Central European countries, including Poland. The aim of our study was to analyse the epidemiology of NRVG in a large tertiary hospital in Warsaw. MATERIAL AND METHODS: We analysed retrospectively data of 63 173 patients aged 0-18 years hospitalized in the period 2006-2010. Nosocomial rotavirus gastroenterocolitis was defined as acute gastroenterocolitis (> 3 loose, or looser than normal, stools in 24 h and/or vomiting), confirmed with rapid immunochromatographic test (BioMaxima, Poland), if symptoms developed > 48 h after admission. RESULTS: In total 575 cases of NRVG were diagnosed. The cumulative attack rate of NRVG was calculated as 0.91% (95% CI: 0.85-0.98%). The incidence density was 2.05/1000 bed-days (95% CI: 0.19-0.22/1000 bed-days). The mean proportion of NRVG among all rotavirus infections was 24%. The highest rates of NRVG were noted at wards where the mean duration of hospital stay was longer than 5 days (General Paediatrics and Neonatal Pathology). Seventy-one percent of children with NRVG were younger than 2 years. The mean duration of hospital stay of children with NRVG was longer than the average duration of hospitalization (11.6 days vs. 4.6 days, p < 0.01). CONCLUSIONS: Our study showed a relevant incidence of NRVG, which can prolong the children's hospital stay. Limiting the number of NRVG is important to improve patients' safety and to avoid additional costs. Routine vaccination against rotavirus diseases could reduce the number of NRVG.

Pandemic influenza in the 2009/2010 season in central Poland: the surveillance study of laboratory confirmed cases.

We retrospectively studied confirmed cases of influenza obligatorily reported to health authorities in central Poland during the 2009/2010 season. Each case was traced and examined with a questionnaire. The samples were tested for influenza A and B by RT-PCR. A total of 561 cases of influenza, including 185 in children under 14 years old, were detected. Four hundred and eighty four people were hospitalized, including 142 children under 14. Thirty two patients died, all with pre-existing risk factors. The most common complications were pneumonia, cardiac arrest, septic shock, circulatory insufficiency, multi-organ failure and myocarditis. The majority of patients (388/484) were treated with oseltamivir. Fifty three patients were mechanically ventilated, 52 patients were given oxygen. Only 11 out of the 561 patients were immunized against seasonal influenza. In conclusion, pandemic influenza affects all age groups, but it is more common in younger patients. Pandemic influenza is becoming an emerging health risk for the Polish population.

Epidemiological and immunological reasons for pertussis vaccination in adolescents and adults.

The resurgence of pertussis has been the subject of considerable debate. Hypotheses to explain increased reporting in developed countries have focused mainly on three aspects: (1) increased recognition of the disease in adolescents and adults; (2) waning of vaccine-induced immunity and (3) loss of vaccine efficacy due to an antigenic shift of Bordetella pertussis. Waning immunity after vaccination or natural infection combined with the absence of regular boosters either in the form of vaccine boosters or natural exposure to B. pertussis - due to the low circulation of the bacterium in well-immunized populations - has been suggested to explain this shift in the age distribution of pertussis. The highest incidence of the disease is currently reported among adolescents and adults who may additionally serve as the source of infection for susceptible infants. Immunological and epidemiological data indicates the need for a universal booster vaccination against pertussis for adolescents and adults.

Epidemiology of pertussis in an urban region of Poland: time for a booster for adolescents and adults.

Since the last decades, an increase of reported incidence of pertussis has been observed in many countries, including Poland, despite high vaccination coverage among infants and children. Before the vaccinations era, pertussis was a major cause of morbidity and mortality among infants and young children. Currently, pertussis is increasingly reported in adolescents and adults. The objective of this paper was to present the epidemiology of pertussis in Mazovian region in Poland in years 2005-2009. In this report we analyzed retrospectively the epidemiological data collected by the Sanitary Station in Warsaw, Poland. A total of 1,455 cases of pertussis were reported in the Mazovian region of Poland in the years 2005-2009. The incidence of pertussis ranged from 2.4/100,000 (2006) to 7.9/100,000 (2008). The incidence was the highest in two groups: infants (>1 year of age; from 13.3/100,000 in 2005 to 32.7/100,000 in 2007) and teenagers (age of 10-14 years; from 11.8/100,000 in 2006 to 68.5/100,000 in 2008). The highest proportion of cases was also reported in the 10-14 years age-group (from 26.4% in 2009 to 46.0% in 2008). The number of hospitalizations due to pertussis ranged from 137 (2005) to 46 (2006), while the percentage of cases requiring hospitalization ranged from 37% (2005) to 25% (2007 and 2008). Three hundred ninety two (27%) cases of pertussis were reported among patients with negative or not confirmed history of pertussis vaccination. We conclude that there is an urgent need for booster vaccination against pertussis in adolescents and adults in Poland.

Influence of rapid influenza test on clinical management of children younger than five with febrile respiratory tract infections.

Children are an important vector for spreading influenza and they are at increased risk for complications. The appropriate diagnosis of influenza may help start early antiviral treatment and may optimize the use of antibiotics and additional laboratory tests. The objective of this study was to describe the influence of rapid influenza detection test (RIDT) on clinical management of children with acute febrile respiratory tract infections. The method consisted of a prospective, open, cohort study conducted in three primary care clinics in Warsaw, Poland, during the epidemic influenza seasons of 2009/2010 and 2010/2011. A total number of 256 children of the age 0-5 years with symptoms of febrile respiratory tract infection were enrolled into the study. A 115 of them were tested with RIDT (BD Directigen EZ FluA + B) and another 141 children, who were not tested, constituted a control group. We found that RIDT gave positive results in 35 (30%) out of the 115 tested children. Antibiotics, additional blood tests and urinalysis were administered more often in the control group compared with the rapid test group (16% vs. 7%; 14% vs. 5%, and 47% vs. 32%, respectively). Chest radiograms were made only in six cases of children from the control group. We conclude that in children with symptoms of acute febrile respiratory tract infection, the rapid influenza detection test provides a rational use of antivirals, reduces an inappropriate use of antibiotics, and decreases a number of additional tests conducted.

Influenza immunization rates in children and teenagers in Polish cities: conclusions from the 2009/2010 season.

The aim of this study was to determine influenza vaccine coverage among children aged 0-18 years in inner city practices in Poland in the 2009/2010 season and factors that might have influenced low vaccination coverage. A retrospective review of 11,735 vaccination charts of children aged 0-18 from seven randomly selected general practices in the capital city of Warsaw and one large practice in the city of Wroclaw was performed. We calculated the numbers of children who were vaccinated in the 2009/2010 season and analyzed the age distribution of vaccinated children. We also reviewed the vaccination history in patients who were vaccinated against influenza including: previous influenza vaccinations, modification (widening) of standard immunization scheme, and a proportion of children who completed the recommended two-dose schedule of vaccination. In the calculations, 95% confidence intervals were used. Out of the total of 11,735 children surveyed, 362 (3.1%, CI: 2.8-3.4%) were vaccinated against influenza in the 2009/2010 season. For 115 of these 362 (31.8%, CI: 27.0-36.6%) children it was their first vaccination against influenza. The mean age of a vaccinated child was 6.0 ± 4.3 years. Children aged 2-5 were most commonly vaccinated (153/362, 42.3%, CI: 37.2-47.4%), while infants (aged 6-12 months) were vaccinated rarely (15/362, 4.4%, CI: 2.2-6.2%). In the group of children younger than 8 years (86/362 children) who were vaccinated for the first time in their life only 29/86 (33.7%, CI: 23.7-43.7%) completed the recommended two-dose schedule. In conclusion, the importance of vaccinating children against influenza is hugely understated in Poland. General physicians should actively recommend annual influenza immunization of children. Recommendations of National Immunization Program concerning influenza vaccine should be clearer, simpler, and easier to implement.

Nosocomial rotovirus gastroenetrocolitis in children hospitalized primarily due to respiratory infections.

Rotaviruses are the leading cause of community-acquired and nosocomial gastroenterocolitis in children. There is little data concerning the epidemiology of nosocomial rotavirus gastroenterocolitis (NRVG) in Central European countries. The aim of our study was to analyze the epidemiology of NRVG in a pediatric hospital in Warsaw, Poland, where the majority of children was admitted due to respiratory tract infections. Retrospective chart analysis of 49,697 patients aged 0-18 hospitalized during 2006-2009 was performed. NRVG was defined as acute gastroeneterocolitis (>3 loose stools in 24 h or vomiting), confirmed with A rapid immunochromatographic test, if symptoms developed >48 h after admission. In total, 469 cases of NRVG were diagnosed. The cumulative attack rate of NRVG for the hospital was calculated as 0.97% (CI 0.86-1.02), the cumulative incidence density was 2.07/1000 bed-days (CI 2.01-2.13). The majority of NRVG were diagnosed at the General Pediatrics Ward (206 cases, 44%) and Allergology and Pulmonology Ward (122 cases, 26%), where the mean duration of hospital stay was longer than 5 days (9.9 ± 1.0 and 6.1 ± 0.8 days, respectively). Primary causes of hospitalization of the children with nosocomial rotavirus gastroenterocolitis were respiratory tract infections (including pneumonia, bronchitis, and otitis media) present in 287 cases (61.2%). The nosocomial rotavirus infection was mostly diagnosed among patients aged 6 months - 2 years (201 cases, 42.8%), less common were infections among infants younger than 6 months (133 cases, 28.3%) and children aged 2-6 (115 cases, 24.5%). The mean age of a child with NRVG was 16.2 ± 10.2. In conclusion, rotavirus gastroenteritis is the most important nosocomial infection in children hospitalized due to respiratory tract infections and can prolong their hospital stay.

Cutaneous changes: an initial manifestation of pulmonary Wegener's granulomatosis.

Cutaneous vasculitis can occur as an isolated dermatologic disorder or as manifestation of a potentially life-threatening systemic vasculitis such as Wegener's granulomatosis (WG). The aim of the study was to characterize cutaneous lesions in 66 WG patients (30 female, 36 male) and to assess the viability of skin biopsy the diagnosis of WG. Skin involvement was observed in 21 (32%) WG patients; in 14 (21%) patients as an initial manifestation and in other seven during the diagnosis establishment. Cutaneous lesions included palpable purpura(n=10), subcutaneous nodules(=4), hemorrhagic bullae (n=3), ulcers (n=2), pustules (n=1), pyoderma gangrenosum (n =1). The patient with pulmonary WG can present initially with cutaneous symptoms and positive PR3-ANCA serologic test results. Leukocytoclastic vasculitis (LCV) was the predominant histopathologic pattern.

Thyroid hormone receptor beta (THRB) is a major target gene for microRNAs deregulated in papillary thyroid carcinoma (PTC).

CONTEXT: Loss of the thyroid hormone receptor is common in tumors. In mouse models, a truncated THRB gene leads to thyroid cancer. Previously, we observed up-regulation of the expression of eight microRNAs (miRs) in papillary thyroid carcinoma (PTC) tumors. OBJECTIVE: Our objective was to determine whether THRB might be inhibited by miRs up-regulated in PTC. DESIGN: The potential binding of miR to the 3'-untranslated region of THRB was analyzed in silico. Direct inhibition by miRs binding to the cloned 3'-untranslated region of THRB was evaluated using luciferase assays. Inhibition of endogenous THRB and its target genes (DIO1 and APP) was examined in cell lines transfected by pre-miRs. The impact on thyroid hormone response element (TRE) was evaluated in promoter assays. Correlations between the expression of THRB and miRs was evaluated in 13 PTC tumor/normal tissue pairs. RESULTS: THRB contains binding sites for the top seven miRs up-regulated in PTC (P = 0.0000002). Direct interaction with THRB was shown for miR-21 and miR-146a. We observed lower levels of THRB transcripts in cell lines transfected with miR-21, -146a, and -221 (down-regulation of 37-48%; P < 0.0001), but not with miR-181a. THRB protein was suppressed down to 10-28% by each of four miRs. Concomitant expression of DIO1 and APP was affected (down-regulation of 32-66%, P < 0.0034 and up-regulation of 48-57%, P < 0.0002, respectively). All four miRs affected TRE activity in promoter assays. Down-regulation of luciferase occurred after transfection with pTRE-TK-Luc construct and each of four miRs. The analysis of tumor/normal tissue pairs revealed down-regulation of THRB in 11 of 13 pairs (1.3- to 9.1-fold), and up-regulation of miR-21, -146a, -181a, and -221 in almost all pairs. CONCLUSIONS: MiRs up-regulated in PTC tumors directly inhibit the expression of THRB, an important tumor suppressor gene.