Hypoalbuminemia in COVID-19: assessing the hypothesis for underlying pulmonary capillary leakage.

BACKGROUND: Since the first observations of patients with COVID-19, significant hypoalbuminaemia was detected. Its causes have not been investigated yet. OBJECTIVE: We hypothesized that pulmonary capillary leakage affects the severity of respiratory failure, causing a shift of fluids and proteins through the epithelial-endothelial barrier. METHODS: One hundred seventy-four COVID-19 patients with respiratory symptoms, 92 admitted to the intermediate medicine ward (IMW) and 82 to the intensive care unit (ICU) at Luigi Sacco Hospital in Milan, were studied. RESULTS: Baseline characteristics at admission were considered. Proteins, interleukin 8 (IL-8) and interleukin 10 (IL-10) in bronchoalveolar lavage fluid (BALF) were analysed in 26 ICU patients. In addition, ten autopsy ultrastructural lung studies were performed in patients with COVID-19 and compared with postmortem findings in a control group (bacterial pneumonia-ARDS and H1N1-ARDS). ICU patients had lower serum albumin than IMW patients [20 (18-23) vs 28 (24-33) g L-1 , P < 0.001]. Serum albumin was lower in more compromised groups (lower PaO2 -to-FiO2 ratio and worst chest X-ray findings) and was associated with 30 days of probability of survival. Protein concentration was correlated with IL-8 and IL-10 levels in BALF. Electron microscopy examinations of eight out of ten COVID-19 lung tissues showed loosening of junctional complexes, quantitatively more pronounced than in controls, and direct viral infection of type 2 pneumocytes and endothelial cells. CONCLUSION: Hypoalbuminaemia may serve as severity marker of epithelial-endothelial damage in patients with COVID-19. There are clues that pulmonary capillary leak syndrome plays a key role in the pathogenesis of COVID-19 and might be a potential therapeutic target.

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.

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.

Assessment of risk factors and human papillomavirus (HPV) related pathogenetic mechanisms of CIN in HIV-positive and HIV-negative women. Study design and baseline data of the HPV-PathogenISS study.

OBJECTIVES: In women with HIV-associated immunosuppression, HPV infections have an increased risk of progression to high-grade cervical intraepithelial neoplasia (CIN). With the HAART-induced prolonged survival and more protracted clinical course of AIDS, progression of CIN to cervical cancer (CC) has become a clinically relevant issue, and the mechanisms responsible for HIV-HPV interactions need further elucidation. The study design and analysis of the baseline data of our new project are presented. MATERIAL AND METHODS: This project is a combination of a prospective cohort study of HIV- and HIV+ women, and a retrospective analysis of CIN lesions and cervical cancer. Up to the present, 244 women have been enrolled (17 HIV+) and subjected to epidemiological interview, colposcopic examination, sampling for HPV testing and typing (PCR, InnoLiPA), and HPV serology. The retrospective series of biopsies were analysed for 13 biomarkers (monitoring key molecular events) using immunohistochemistry and tested for HPV by PCR and TaqMan. RESULTS: HIV- and HIV+ women differ in their exposure status to many of the key epidemiological risk factors of cervical cancer, the most significant ones being number of sexual partners (p = 0.0001), age at onset of sexual activity (p = 0.002), and contraception (yes-no) (p = 0.009). The differences in the baseline clinical observations are less dramatic; HIV-positive women had more frequent HSIL PAP tests (p = 0.040), CIN2 or higher in cervical biopsy (p = 0.049), and external genital warts (p = 0.019). The factors predicting intermediate endpoint markers of cervical cancer, i.e., HSIL PAP smear, ATZ2 in colposcopy, and high-grade CIN in biopsy were analysed in univariate and multivariate regression models. All factors significant in univariate analysis were entered in the multivariate model; HIV-status and Pap smear history maintained their independent predictive power of the HSIL Pap test. The most powerful predictor of ATZ2 colposcopy was HSIL in Pap test. Only the HSIL Pap test and ATZ2 colposcopy remained significant independent predictors of high-grade CIN (p = 0.0001 and p = 0.008, respectively) in the multivariate model. CONCLUSIONS: The three intermediate endpoint markers are closely interrelated, but predicted in part by different covariantes in the causal pathway to cervical cancer. To elucidate whether the increased risk of HIV-positive women to high-grade CIN is due a) to their different exposure status to the risk factors, b) to the direct effects of HIV, or c) to molecular interactions between HIV and HPV, we need to complete these analyses separately in HIV+ and HIV- women.

p16(INK4A) expression is related to grade of cin and high-risk human papillomavirus but does not predict virus clearance after conization or disease outcome.

The role of p16(INK4A) as a marker of HR-HPV and in the diagnosis of CIN has been well established, but its predictive value in the clearance of the virus after CIN treatment and its use as a prognostic marker of cervical cancer has not been studied. A series of 302 archival samples, including 150 squamous cell carcinomas (SCCs) and 152 CIN lesions, were subjected to immunohistochemical staining for p16(INK4A) and HPV testing using PCR with three primer sets (MY09/11, GP5/GP6, SPF). Follow-up data were available of 88 SCC patients, and 67 of the CIN lesions had been followed-up with serial PCR after conization. HR-HPV types were closely associated with CIN (OR 19.12; 95%CI 2.31-157.81) and SCC (OR 27.25; 95%CI 3.28-226.09). There was a significant linear relationship between the lesion grade and intensity of p16(INK4A) staining (p = 0.0001). The expression of p16(INK4A) was also closely related to HR-HPV (p = 0.0001). p16(INK4A) staining was a 100% specific indicator of CIN, with 100% PPV, and showed 83.5% sensitivity and 80.1% PPV in detecting HR-HPV. However, p16(INK4A) staining did not predict clearance/persistence of HR-HPV after treatment of CIN. Similarly, despite a slightly more favorable survival in women with strong/intense p16(INK4A) staining in univariate analysis, p16(INK4A) expression was not an independent prognostic predictor in multivariate survival (Cox) analysis. After adjustment for p16(INK4A) staining, HR-HPV, histological grade, International Federation of Gynecology and Obstetrics (FIGO) stage, and age, only the last two were significant prognostic predictors (p = 0.0001 and p = 0.003, respectively). The present data confirm the role of p16(INK4A) as a highly specific marker of CIN and HR-HPV type, but expression of this protein does not seem to be of any prognostic value in cervical cancer or in predicting the clearance of HR-HPV after treatment of CIN. We speculate that different subgroups of cervical cancer are characterized by aberrant p16(INK4A)/cyclin D/Rb pathways that are due to different mechanisms that can be mutually exclusive.

Factors predicting the persistence of genital human papillomavirus infections and PAP smear abnormality in HIV-positive and HIV-negative women during prospective follow-up.

As part of an extensive multi-institutional DIANAIDS study focused on assessing the risk factors, natural history, diagnosis and follow-up of genital human papillomavirus (HPV) infections in HIV-infected women, the present communication reports a sub-cohort of 142 women (89 HIV+ and 48 HIV-), followed-up for a mean of 14.07 (+/-10.84) months to analyse the factors predicting the persistence and clearance of HPV infections (polymerase chain reaction [PCR] and sequencing) and cervical Papanicolaou (PAP) smear abnormalities, using both univariate (Kaplan-Meier) and multivariate (Cox) survival analysis. The appearance of new HPV infections during the follow-up was significantly more frequent in HIV-positive than in HIV-negative women, odds ratio (OR) 8.800 (95% confidence interval [CI]: 1.199-64.611), and also the clearance rate was significantly less frequent in HIV-positive than in HIV-negative women, 69.2% vs 22.8%, respectively (OR 0.330; 95% CI: 0.163-0.670). These two groups were also markedly different with respect to the clinical course of the cervical lesions, in the frequency of progressive disease (determined by PAP smear) was higher in HIV-positive group (12/89) than in HIV-negative women (2/52) (OR 3.506; 95% CI 0.816-15.055) (P = 0.055), in whom the disease regressed more frequently than in HIV-positive women (13.5% vs 7.9%) (OR 0.584; 95% CI 0.217-1.573). Using (1) HPV-positivity, (2) oncogenic HPV-type and (3) significant PAP smear abnormality at the end of follow-up as outcome measures, (1) was significantly (P < 0.001) predicted by the following variables in univariate analysis: age, mode of contraception, CD4 count, and HIV-positivity. The significant predictors of (2) were age and mode of contraception. The outcome measure (3) was significantly predicted by CD4 count, PAP smear abnormality and PCR status at entry. In the multivariate analysis, the significant independent predictive factors for HPV-positivity proved to be only the HIV status (P < 0.001), and PCR status at entry, p53 polymorphism at aa-72, oncogenic HPV type and significant PAP smear at entry remained independent predictors, with the significance level of P < 0.05. None of the significant predictors of oncogenic HPV type in univariate analysis retained their independent value in multivariate analysis. Oncogenic HPV type at entry proved to be an independent predictor of significant PAP smear (P < 0.05). The present results indicate that HIV-infected women, even on highly active antiretroviral therapy, demonstrate a more aggressive clinical course of cervical HPV infections, and fail to eradicate the disease more frequently than HIV-negative women. This persistence of HPV-positivity, oncogenic HPV type and significant PAP smear abnormality can be predicted by the results of PAP test and HPV typing in univariate analyses, and partly retain their independent predictive value also in multivariate analysis. Clearly, in addition to regular monitoring by PAP smear, HPV testing for the oncogenic HPV types seems to provide additional prognostic information in the management of cervical lesions in HIV-infected women.

Cesarean section using the Misgav Ladach method.

OBJECTIVE: To stress the advantages of the Misgav Ladach method for cesarean section. STUDY DESIGN: In this study operative details and the postoperative course of 139 patients who underwent cesarean section according to the Misgav Ladach method in 1995-96 are presented. RESULTS: The Misgav Ladach method reduces operation time, time of child delivery, and time of recovery. The rates of febrile morbidity, wound infection and wound dehiscence are not affected by the new technique. CONCLUSION: Our study highlights the efficiency and safety of the Misgav Ladach method, and points out the speeded recovery, with early ambulation and resumption of drinking and eating, that makes the cesarean section delivery closer and closer to natural childbirth.

Serum 2'-5'-oligoadenylate synthetase levels and clinical response to interferon-beta therapy in women with genital human papillomavirus infection.

To investigate the activity of parenterally administered interferon-beta (IFN-beta) in women with genital human papillomavirus (HPV) infection, serum 2'-5'-oligoadenylate synthetase (2'-5'OAS), an enzyme induced by IFNs, was measured before, during, and after therapy. Serum levels of 2'-5'OAS significantly increased during therapy (P = .005). The patients classified as not responding to treatment at 3 months of follow-up had baseline levels of 2'-5'OAS significantly higher than those who responded to treatment (P = .0011). Differences between the IFN-beta-treated group and untreated controls appeared at day 6 (P = .0019). 2'-5'OAS is a useful parameter in monitoring parenterally administered IFN-beta. The data suggest that women with genital HPV infection and elevated baseline levels of 2'-5'OAS are unlikely to respond to therapy with IFN-beta.

Risk factors for respiratory distress syndrome in the newborn. A multicenter Italian survey. Study Group for Lung Maturity of the Italian Society of Perinatal Medicine.

Risk factors for respiratory distress syndrome (RDS) in the newborn have been evaluated using data from a large survey conducted between 1980 and 1989 in selected periods in eleven perinatal units placed in five Italian regions. A total of 1624 liveborn infants consecutively delivered at the collaborating centers, at delivery 26-37 weeks gestational age and without clinically evident congenital anomalies were included in the survey. All the newborns were followed up to the 28th day of life. A total of 131 newborns (7.8%) developed RDS. Overall 1st-7th and 1st-28th day of life infant mortality rates were 54.8 and 61.6/1,000 livebirths; the corresponding rates in babies who developed RDS were 419.8 and 465.6/1,000 livebirths. The frequency of RDS was higher in males than in females and the corresponding relative risk, RR, was 0.7, with 95% confidence interval, CI, ranging from 0.5 to 0.9. The risk of RDS markedly increased with decreasing birth weight: compared to babies weighing more than 2500 g at birth the RR estimates were respectively 1.4, 4.5, 8.8 and 39.3 in those weighing > 2000-2500 g, > 1500-2000 g, > 1000-1500 g and 1000 g or less. Likewise, compared to babies born between the 35th and the 37th week of gestation, the RR of RDS was 3.3 and 21.5 in those born between the 31st-34th or before the 31st week of gestation. Multiple pregnancy, gestational or chronic diabetes, pregnancy-induced or chronic hypertension and premature rupture of the membranes were not related to the risk of RDS.(ABSTRACT TRUNCATED AT 250 WORDS)

HPV, HIV infection, and risk of cervical intraepithelial neoplasia in former intravenous drug abusers.

The relation between human immunodeficiency virus (HIV), human papilloma virus (HPV) infection, sexual habits, reproductive history, and risk of cervical intraepithelial neoplasia (CIN) has been analyzed in a cross-sectional study conducted since 1986 among female former intravenous drug abusers attending for the first time to the Colposcopic Unit of the Ospedale Luigi Sacco of Milan and women consecutively admitted to the Community for Past Drug Abusers, S. Patrignano, Rimini. A total of 434 subjects entered the study; of those 128 (30%) had a diagnosis of CIN. Compared with HIV-negative subjects, odds ratio (OR) of CIN was 8.0 (95% confidence interval (CI) 4.6-14.1) for HIV-positive ones and the frequency of CIN 2 and 3 was higher in HIV-positive than that in HIV-negative subjects (chi 2(1), trend, 6.67, P 0.01). Compared with women without current HPV infection the OR estimate was 38.0 (95% CI 20.3-71.2) in those with current diagnosis of HPV infection. Considering HIV-positive subjects only, the frequency of CIN increased with stage of HIV infection and was higher in women with lower CD4+ values. Finally, no relation emerged between CIN risk and age, indicators of sexual habits, oral contraceptive use, parity, and history of spontaneous or induced abortions.

[Sex behavior and sexually transmitted diseases in drug-dependent women: study of 465 cases]. / Comportamento sessuale e malattie sessualmente trasmesse nelle donne tossicodipendenti: studio su 465 casi.

465 intravenous drug abuser (IVDA) women were studied to evaluate the prevalence of sexually transmitted diseases, 2207 university students have been considered as control group. A complete gynecological evaluation with Pap smear and cervico-vaginal cultures were performed. Informations on sexual and behavioural patterns were collected using a standard questionnaire. IVDAs show early onset of sexual activity (15 vs. 18 yrs) and many sexual partners; just a small percentage of them use condom, efficacious in the protection against venereal diseases. These peculiar behavioural patterns and the immunodeficiency ascribable to the drug abuse may condition the high frequency of viral and bacterial infections of lower genital tract (53% vs 0.8% and 67% vs 10% respectively). Cervical intraepithelial neoplasia has been found significantly more frequently in IVDA women (16%) than in control group (1%) p less than .01.

Effect of cigarette smoking on plasmatic regulation of vascular prostacyclin in pregnancy and puerperium.

Prostaglandins, particularly prostacyclin, participate in the control of fetal and maternal circulations. In the present study the effect of cigarette smoking on plasma prostacyclin-stimulating activity during late pregnancy and the puerperium (four to six months) and in the newborns was assessed. Plasma samples from 22 apparently healthy nonsmokers and 17 smokers (more than 15 cigarettes per day) were obtained twice during pregnancy and once after delivery. Plasma samples from nine infants born to smokers and seven infants born to nonsmokers were obtained 72 to 96 hours after birth. Plasma activity was evaluated by incubating the plasma samples with cultured rat aortic smooth muscle cells and measuring the prostacyclin released in the culture medium by specific radioimmunoassay of its stable metabolite, 6-keto-prostaglandin F1 alpha. In all of the women, plasma activity did not change significantly during pregnancy or after delivery. In smokers, plasma activity was always lower than in nonsmokers, but not significantly so. The plasma activity of infants born to smokers was significantly lower than that of infants born to nonsmokers.