Airway pathology in severe asthma is related to airflow obstruction but not symptom control.

BACKGROUND: Patients with asthma present structural and inflammatory alterations that are believed to play a role in disease severity. However, airway remodeling and inflammation have not been extensively investigated in relation to both symptom control and airflow obstruction in severe asthmatics. We aimed to investigate several inflammatory and structural pathological features in bronchial biopsies of severe asthmatics that could be related to symptom control and airflow obstruction after standardized treatment. METHODS: Fifty severe asthmatics received prednisone 40 mg/d for 2 weeks and maintenance therapy with budesonide/formoterol 400/12 µg twice daily + budesonide/formoterol 200/6 µg as needed for 12 weeks. Endobronchial biopsies were performed at the end of 12 weeks. We performed extensive immunopathological analyses of airway tissue inflammation and remodeling features in patients stratified by asthma symptom control and by airflow obstruction. RESULTS: Airway tissue inflammation and remodeling were not associated with symptom control. Asthmatics with persistent airflow obstruction had greater airway smooth muscle (Asm) area with decreased periostin and transforming growth factor beta-positive cells within Asm bundles, in addition to lower numbers of chymase-positive mast cells in the submucosa compared to patients with nonpersistent obstruction. CONCLUSIONS: Symptom control in severe asthmatics was not associated with airway tissue inflammation and remodeling, although persistent airflow obstruction in these patients was associated with bronchial inflammation and airway structural changes.

Trend of decreasing length of cervical cone excision during the last 20 years.

OBJECTIVE: The aim of the present investigation was to evaluate the cervical conizations performed in the last 20 years in a single institution, with a particular interest in analyzing the trend of the length of cone excisions. PATIENTS AND METHODS: A retrospective cohort study of women who underwent a CO2-laser cervical conization between January 1996 and December 2015. Cytological abnormalities on referral pap smear, colposcopic findings and pertinent clinical and socio-demographic characteristics of each woman were collected. In particular, the length of cone specimen was evaluated, taking into account all the factors potentially influencing the length of excision. RESULTS: A total of 1270 women who underwent cervical conization from January 1996 to December 2015 were included in the analysis. A mean cone length of 15.1 ± 5.7 mm was reported, and we observed a significant decrease in the length of cone excisions over the whole study period. Age (rpartial = 0.1543, p < 0.0001), see & treat procedure (rpartial = -0.1945, p < 0.0001) and grade II colposcopic findings (rpartial = 0.1540, p < 0.0001) were significantly associated with the length of cone excision on multivariate analysis. CONCLUSIONS: In the last 20 years, a significant decrease in the length of cone excision was observed. In our opinion, this can be due to the acquired awareness by the gynecologists of the potential disadvantages of wide cone excision in term of adverse obstetric outcomes in future pregnancies.

Colposcopic patterns of vaginal intraepithelial neoplasia: a focus on low-grade lesions.

OBJECTIVE: The aim of this study was to evaluate the colposcopic patterns observed in women with a histopathological diagnosis of vaginal intraepithelial neoplasia, with a particular interest in analyzing the colposcopic characteristics of low-grade squamous intraepithelial lesions (LSIL). PATIENTS AND METHODS: Medical charts and colposcopy records of women diagnosed with vaginal intraepithelial neoplasia from January 1995 to December 2015, were analyzed in a multicenter retrospective case series. The abnormal colposcopic patterns observed in women with vaginal LSIL and vaginal high-grade SIL (HSIL) were compared. The vascular patterns and micropapillary pattern were considered separately. RESULTS: Regardless the histopathological grading, in women with vaginal SIL, the grade I abnormal colposcopic findings were more frequent than grade II abnormalities. However, a grade I colposcopy was more commonly observed in women with a biopsy diagnosis of LSIL rather than HSIL (p<0.0001). Similarly, the micropapillary pattern was more frequently observed in women with LSIL (p=0.004), while vascular patterns were observed more frequently in women diagnosed with vaginal HSIL (p<0.0001). In women with grade I colposcopy, the menopausal status and a previous hysterectomy appeared to be associated with the diagnosis of vaginal HSIL. CONCLUSIONS: Grade I abnormal colposcopic findings were more commonly observed in women with vaginal LSIL, as well as the micropapillary pattern. On the other hand, grade II abnormal colposcopy and the presence of vascular patterns were more frequently observed in women with vaginal HSIL.

Detection of occult endocervical glandular dysplasia in cervical conization specimens for squamous lesions.

The aim of this work was to evaluate the incidence of occult cervical glandular intraepithelial neoplasia (CGIN) and adenocarcinoma of the cervix (AC) in women treated with CO2-laser conization for cervical intraepithelial neoplasia (CIN) or squamocellular cervical cancer (SCC). The medical records of all women with a histological diagnosis of squamous lesions of the uterine cervix (persistent CIN1, CIN2, CIN3 and SCC) who were subsequently treated with CO2-laser conization at our institution, during the period from January 1991 to December 2014, were analyzed in a retrospective case series. Among the 1004 women fulfilling the study inclusion/exclusion criteria, 77 cases (7.7%) of occult glandular lesions (CGIN and AC) were detected on the final cone specimen (48 cases of occult low-grade cervical glandular intraepithelial neoplasia (LCGIN), 25 cases of occult high-grade cervical glandular intraepithelial neoplasia (HCGIN), and four cases of occult "usual-type" AC). No difference in the mean age between women diagnosed with occult glandular lesions and women without occult glandular lesions on the final specimen emerged (39.1±9.3 vs 38.4±9.4, p=0.5). In women with occult LCGIN on cone specimen, mean follow-up of 48 months was reported (range 7-206 months) and no cases of progression to HCGIN or AC were observed. In conclusion, a relatively high rate of occult glandular lesions was found in women treated for squamous lesions. The natural history of CGIN is still uncertain and, in particular, there are some controversies as to whether LCGIN is a precursor lesion of HCGIN or AC. In this context the role of pathologists become very important since the appropriate diagnosis of these lesions could have potential implications in the clinical management of these patients.

High-grade vaginal intraepithelial neoplasia and risk of progression to vaginal cancer: a multicentre study of the Italian Society of Colposcopy and Cervico-Vaginal Pathology (SICPCV).

OBJECTIVE: The aim of this study was to analyse the women with high grade vaginal intraepithelial neoplasia (HG-VaIN), in order to identify a subset of women at higher risk of progression to invasive vaginal cancer. MATERIALS AND METHODS: The medical records of all the women diagnosed with HG-VaIN, and subsequently treated, from January 1995 to December 2013 were analyzed in a multicentre retrospective case series. The rate of progression to invasive vaginal cancer and the potential risk factors were evaluated. RESULTS: 205 women with biopsy diagnosis of HG-VaIN were considered, with a mean follow up of 57 months (range 4-254 months). 12 cases of progression to vaginal squamocellular cancer were observed (5.8%), with a mean time interval from treatment to progression of 54.6 months (range 4-146 months). The rate of progression was significantly higher in women diagnosed with VaIN3 compared with VaIN2 (15.4% vs. 1.4%, p < 0.0001). Women with HG-VaIN and with previous hysterectomy showed a significantly higher rate of progression to invasive vaginal cancer compared to non-hysterectomised women (16.7% vs. 1.4%, p < 0.0001). A higher risk of progression for women with VaIN3 and for women with previous hysterectomy for cervical HPV-related disease was confirmed by multivariable logistic regression analysis. CONCLUSIONS: A higher rate of progression to vaginal cancer was reported in women diagnosed with VaIN3 on biopsy and in women with previous hysterectomy for HPV-related cervical disease. These patients should be considered at higher risk, thus a long lasting and accurate follow up is recommended.

Toll-like receptors 2, 3 and 4 and thymic stromal lymphopoietin expression in fatal asthma.

BACKGROUND: Airway inflammation in asthma involves innate immune responses. Toll-like receptors (TLRs) and thymic stromal lymphopoietin (TSLP) are thought to be involved in airway inflammation, but their expression in asthmatics' both large and small airways has not been investigated. OBJECTIVE: To analyse the expression of TLR2, TLR3, TLR4 and TSLP in large and small airways of asthmatics and compare their expression in smoking and non-smoking asthmatics; to investigate whether TLR expression is associated with eosinophilic or neutrophilic airway inflammation and with Mycoplasma pneumoniae and Chlamydophila pneumoniae infection. METHODS: Using immunohistochemistry and image analysis, we investigated TLR2, TLR3, TLR4 and TSLP expression in large and small airways of 24 victims of fatal asthma, FA, (13 non-smokers, 11 smokers) and nine deceased control subjects (DCtrl). TLRs were also measured in 18 mild asthmatics (MA) and 12 healthy controls (HCtrl). M. pneumoniae and C. pneumoniae in autopsy lung tissue were analysed using real-time polymerase chain reaction. Airway eosinophils and neutrophils were measured in all subjects. RESULTS: Fatal asthma patients had higher TLR2 in the epithelial and outer layers of large and small airways compared with DCtrls. Smoking asthmatics had lower TLR2 levels in the inner and outer layers of the small airways than non-smoking asthmatics. TSLP was increased in the epithelial and outer layers of the large airways of FA. FA patients had greater TLR3 expression in the outer layer of large airways and greater TLR4 expression in the outer layer of small airways. Eosinophilic airway inflammation was associated with TLR expression in the epithelium of FA. No bacterial DNA was detected in FA or DCtrls. MA and HCtrls had only a small difference in TLR3 expression. CONCLUSIONS AND CLINICAL RELEVANCE: Increased expression of TLR 2, 3 and 4 and TSLP in fatal asthma may contribute to the acute inflammation surrounding asthma deaths.

Phenanthrene decreases neutrophil function by disrupting intracellular redox balance.

The aim of the present work was to evaluate whether the treatment of human neutrophils with phenanthrene (PHN) can alter the phagocytic and microbicidal capacity of these cells by causing a disruption in redox balance. Peripheral neutrophils from healthy subjects were treated for up to 24 h with increasing concentrations of phenanthrene. Phagocytic/microbicidal activities, antioxidant enzymes, oxidative lesions (thiobarbituric acid-reactive substances and protein thiol and carbonyl groups) and redox signaling compounds (intracellular Ca(2+), superoxide, hydrogen peroxide and nitric oxide) were monitored on neutrophils exposed to 10 microg PHN ml(-1). Cell viability decreased abruptly at PHN concentrations above 10 microg ml(-1) (LC50 = 20.86 +/- 0.51 microg ml(-1) and p-sigmoidal slope = 19.88 +/- 10.11). Phagocytic and microbicidal capacities were decreased by 60 and 82%, respectively. Substantial increases in total-/Mn-SOD, catalase, glutathione peroxidase and glutathione reductase activities (by 61, 15, 87, 245 and 70%, respectively) matched the oxidative injury obtained in TBARS (2.5-fold higher) and protein thiol (54% lower). Diminished productions of superoxide by 18% and hydrogen peroxide by 29% were observed in association to exacerbated calcium (27%) and nitric oxide (63%) levels. The data indicate that phenanthrene might be associated with substantial reduction in human neutrophil functions due to severe intracellular redox imbalances.

Effects of potassium dichromate on nucleic acid and protein syntheses and on precursor uptake in BHK fibroblasts.

Treatments for 1 to 4 hr with 10-4 m potassium dichromate, a soluble hexavalent chromium salt with a strong oxidizing power, markedly reduce DNA and RNA accumulation rates in hamster fibroblasts grown in vitro (BHK line), as shown by quantitative spectrophotometric determinations. Such inhibitory action is not immediately evident on the basis of the incorporation rates of labeled nucleosides into DNA and RNA, as dichromate affects also the relative concentrations of labeled precursors in the intracellular pool. Dichromate first stimulates and then inhibits nucleoside (mostly thymidine) uptake, whereas amino acid uptake is immediately inhibited. Actual rates of macromolecular syntheses have been calculated by taking into account the induced changes of soluble precursor concentrations; sucn normalized rates point out that dichromate induces a sudden blockage of DNA replication, whereas RNA and protein syntheses are secondarily inhibited. The observed cytotoxic effects of dichromate are tentatively referred to the oxidation of cell components by hexavalent chromium and thereby to the interaction of reduced trivalent chromium with specific biological ligands on cell membrane and on DNA.

Inhibition of DNA synthesis in BHK fibroblasts treated in vitro with potassium dichromate.

Treatment of hamster fibroblasts with potassium dichromate in vitro stimulates tritiated thymidine uptake into the intracellular nucleotide pool. This effect is due to the oxidizing action of hexavalent chromium on the plasma membrane. Dichromate, induces also an inhibition of DNA replication, which is due to the interaction of reduced trivalent chromium with specific biological ligands on the DNA molecule.