Progress in the development of ß-lactams as N-Acylethanolamine Acid Amidase (NAAA) inhibitors: Synthesis and SAR study of new, potent N-O-substituted derivatives.

The anti-inflammatory effects resulting from raising the levels of palmitoylethanolamide (PEA), an endogenous bioactive lipid, led to envisage N-Acylethanolamine Acid Amidase (NAAA), the cysteine hydrolase mainly responsible for PEA degradation, as an attractive target for small molecule inhibitors. Previous work in our group identified serine-derived ß-lactams as potent and systemically active inhibitors of NAAA activity. Aiming to expand the SAR study around this class of compounds, we investigated the effect of the substitution on the endocyclic nitrogen by designing and synthesizing a series of N-substituted ß-lactams. The present work describes the synthesis of new N-O-alkyl and N-O-aryl substituted ß-lactams and reports the results of the structure activity relationship (SAR) study leading to the discovery of a novel, single-digit nanomolar NAAA inhibitor (37). Compound 37 was shown in vitro to inhibit human NAAA via S-acylation of the catalytic cysteine, and to display very good selectivity vs. human Acid Ceramidase, a cysteine amidase structurally related to NAAA. Preliminary in vivo studies showed that compound 37, administered topically, reduced paw edema and heat hyperalgesia in a carrageenan-induced inflammation mouse model. The high in vitro potency of 37 as NAAA inhibitor, and its encouraging in vivo activity qualify this compound as a new tool for the study of the role of NAAA in inflammatory and pain states.

The sentinel lymph node biopsy for breast cancer over the years.

The sentinel lymph node biopsy (SLNB) has progressively substituted complete axillary lymph node dissection (CALND), and has dramatically changed breast surgery impact on women's psychophysical wellness, reducing surgical morbidity while granting an adequate nodal staging. The present authors have seen a gradual improvement in the technique in order to reduce both surgical time and the number of interventions required, in particular with the intraoperative histological examination of sentinel node. Anyway, there is still great debate about the predictability of axillary nodal status in case of negative SLNB, as well as in case of positive one. Therefore, the authors reviewed the SLNB history and discussed its controversial points.

First generation prophylactic HPV vaccines: the state of the art.

A chronic infection with "high risk" human papillomavirus (HPV) is as an obligated step in the development of cervical dysplasia and cancer and, less frequently, other types of cancers. It has been suggested to be responsible for an estimated 100% of cases of cervical cancer, 90% of anal cancers, 40% of vulvar, vaginal and penile cancers and very likely about 18% of oropharyngeal cancers. Furthermore, infection with "low risk" HPV types is responsible for some benign conditions such as genital warts and recurrent respiratory papillomatosis. Even if it is only very rarely a causative factor leading to cancer, these benign diseases have a high socio-economic impact. HPV vaccination has been shown to be viable method in the prevention of HPV-related pathologies. Currently, there are two vaccine formulas belonging to the very low particles (VLPs) first generation vaccines. The first is the bivalent vaccine Cervarix®, which is active against high risk HPV 16 and 18. The second is the quadrivalent vaccine Gardasil®, which is active against high risk HPV 16 and 18, as well as against the low risk HPV types 6, 11. In this paper, we will discuss typical HPV-related pathologies, the effectiveness of these two first generation vaccines, existing advices, potential side effects and limits as well as new directions for HPV-vaccines implementation.

Isolated axillary nodal swelling and cancer of unknown primary.

INTRODUCTION: The literature reports rare cases of isolated axillary lymph node metastasis from cancer of unknown primary (CUP). The authors reviewed the prevalence and outcome of patients with isolated axillary nodal swelling suspicious for malignancy affected or not by isolated axillary node metastasis from CUP. MATERIALS AND METHODS: The authors collected data about 65 patients presented with isolated axillary lymph node swelling who underwent axillary lymph node excisional biopsy for malignancy suspicion, between January 2005 and December 2011, in the absence of any specific diagnosis. RESULTS: Histological examination revealed a metastatic infiltration by an occult solid cancer in 16 cases (24%), ten of which were occult breast cancers. Histological patterns and molecular markers allowed in all cases of occult cancer a probable identification of the primary tumor site, while a definitive diagnosis was possible only in the 56.25% of cases (9/16). The prognosis of these patients was very poor with a five-year overall survival of 28%, and thus very similar to patients affected by Stage IV overt breast cancer. CONCLUSIONS: Among occult malignancies presenting with sole axillary lymph node metastasis, breast cancer remains the more probable primary cancer, but many other sites should be taken into consideration by negative breast imaging. Positron-emission tomography computed tomography (PET-CT) resulted helpful in the primary site detection, but has nonetheless a margin of failure. Occult breast cancers behave very similar to Stage IV overt breast cancers, and should be treated accordingly.

Laparoscopic peritoneal lavage for perforated colonic diverticulitis: a definitive treatment? Retrospective analysis of 63 cases.

BACKGROUND: The ideal treatment of perforated diverticulitis and the indications for elective colon resection remain controversial. Considering the significant morbidity and mortality rates related to traditional resection, efforts have been made to reduce the invasiveness of surgery in recent decades. Laparoscopic peritoneal lavage has emerged as an effective alternative option. We retrospectively investigated the effectiveness of laparoscopic peritoneal lavage for perforated diverticulitis and the possibility that it could be a definitive treatment. METHODS: We included patients treated with laparoscopic peritoneal lavage for perforated diverticulitis. The inclusion criteria were all emergency patients with generalized peritonitis due to Hinchey III perforated diverticulitis and some cases of Hinchey II and IV. RESULTS: Sixty-three patients were treated with laparoscopic peritoneal lavage. Six patients (9.5 %) had Hinchey II diverticulitis; 54 patients (85.7 %) had Hinchey III; and three patients (4.8 %) had Hinchey IV. The mean operative time was 87.3 min (±25.4 min), and the overall morbidity rate was 14.3 %. One patient died because of pulmonary embolism, and there were six early reinterventions because of treatment failure. Delayed colon resection was performed in four of the remaining 57 patients (7 %) because of recurrent diverticulitis. In the other 53 patients (93 %), we saw no recurrence of diverticulitis and no intervention was performed after a median follow-up period of 54 months (interquartile range 27-98 months). CONCLUSIONS: Laparoscopic peritoneal lavage for perforated diverticulitis can be considered a safe and effective alternative to traditional surgical resection, and using this approach, most elective colon resection might be avoided.

Second trimester amniotic fluid retinol in patients developing preeclampsia.

BACKGROUND: Retinol (ROH) is an essential micronutrient required for normal fetal development and an essential molecule for antioxidant processes. OBJECTIVE: To investigate the putative role of ROH as a marker of preeclampsia in early second trimester amniotic fluid (AF). MATERIALS AND METHODS: Case-control study comparing the concentration of ROH and other antioxidants such as uric acid, vitamin E and malondialdehyde (MDA) in second trimester AF in patients that later developed preeclampsia with normal pregnancies. RESULTS: The concentration of ROH in amniotic fluids of women that later developed preeclampsia was significantly higher than those of uncomplicated pregnancies (66.72 µg/l (49.00-70.56) vs. 44.4 µg/l (31.9-51.17), p < 0.05). No statistical significant difference was found in uric acid, vitamin E and MDA concentration. In the multivariate logistic regression, concentrations of ROH in amniotic fluids directly correlate with the risk of developing preeclampsia (OR 1.13, IC 0.01-1.26, p < 0.05). CONCLUSIONS: Second trimester AF ROH concentration was significantly higher in pregnancies that developed preeclampsia compared to normal pregnancies.

Therapy side-effects and predictive factors for preterm delivery in patients undergoing tocolysis with atosiban or ritodrine for threatened preterm labour.

The objective of this study was to compare the safety and efficacy of atosiban and ritodrine in the treatment of threatened preterm labour (TPL) and to analyse the predictive factors of preterm delivery. We retrospectively sampled data on 380 women hospitalised for TPL (24-35 weeks' gestation), in our clinic between 2004 and 2007. All were subjected to tocolysis with ritodrine and/or atosiban. Data were analysed using R (version 2.12.1), considering p < 0.05 as significant. We had 69 women treated with atosiban, 242 treated with ritodrine and 69 treated with ritodrine changed for atosiban, if adverse effects occurred. In the multivariate logistic regression, the use of atosiban vs ritodrine does not play any role in delaying delivery after 48 h or 7 days, whereas the cervical change at the digital examination, high contractions pre/post-therapy ratio, pPROM, cervical length and fibronectin result as predictive factors for both delivery before 48 h or 7 days. Maternal adverse drug effects were significantly more frequent in patients treated with ritodrine, and one single case of pulmonary oedema was observed. We found fewer side-effects in the atosiban than in the ritodrine group and no difference in efficacy. Moreover, the most predictive factors for preterm delivery were fibronectin test, pPROM, digital vaginal examination and uterine contraction persistence. We believe that predictive capacity of these tests could give the opportunity for targeting therapy and limiting drug side-effects and cost.

New surgical trends in breast cancer treatment: conservative interventions and oncoplastic breast surgery.

AIM: From radical mastectomy by Halstedt to quadrantectomy by Veronesi, surgical treatment of breast cancer has become more and more conservative in order to preserve women quality of life. We analyzed the evolution of breast interventions through a nine-year period. METHODS: We collected data about all breast surgery interventions performed between 2002 and 2010 in our Department Of Surgery, focusing on patients' age, tumor histology, TNM classification, hormonal status, intervention radicality on the breast and axilla, and eventual plastic surgery. Data were analyzed by R (version 2.14.2), considering significant P<0.05. RESULTS: A total of 3320 breast surgery interventions were performed on 2300 patients. Absolute yearly number of interventions has strongly increased with the introduction of the mammography screening (291 to 430). Conservative breast surgery (55% to 62%) and skin-sparing mastectomy (1% to 8%) have been performed more frequently in premenopausal patients, and significantly increased in time, with a consequent decrease of classical radical mastectomy (38 to 15%) but an increase of margins widening after primary surgery (2% to 6%). Sentinel lymph node biopsy is mostly replacing complete axillary lymph node dissection (93% to 31%). Skin-glandular reshaping progressively increased (up to 20%) as also breast reconstruction (23% to 40%), which since 2008 has been performed also in women older than 75 years, while flaps have been used in strictly selected patients. CONCLUSION: Conservative surgery represents the target of current breast cancer treatment where possible, and skin-sparing mastectomy an interesting alternative to classical one when radicality is required. Sentinel lymph node biopsy has replaced complete axillary lymph node dissection by clinically negative nodal status. Breast reshaping and reconstruction are increasing in every age group, including women older than 75 years.

Fertility in women survivors of hematological malignancies: what is the real role of GnRH analogue treatment?

PURPOSE OF INVESTIGATION: The aim of this study was to evaluate the ovarian function in women who received or not gonadotropin-releasing hormone (GnRH) analogue co-treatment compared to the control group that did not receive it. MATERIALS AND METHODS: This study analyzed 124 patients affected by hematological diseases between 1998 and 2007. The data were analyzed using R (v 2.9.1). RESULTS: In the women treated with GnRH analogue, the authors found 33% post-treatment secondary amenorrhea and 6% had a pregnancy post-treatment, while in the other group the prevalence were respectively 49% and 4% (p n.s.). Moreover, in multivariate analysis the authors found bone marrow transplantation to be a risk factor for secondary amenorrhea, while the association of chemotherapy with radiotherapy was a protective factor (p < 0.05). Finally, none of the considered factors were predictive of pregnancy achievement post-treatment. CONCLUSIONS: The authors found no statistical evidence to support that Gn-RH analogue treatment preserves ovarian follicular reserve during hematologic cancer treatment, but more evidence must be obtained.

Breast-feeding and benign breast disease.

Benign breast disease (BBD) is very common among women in their fertile age, but its correlation with breast reproductive function remains unclear. Our study aimed to investigate the relation between BBD and breast-feeding. We collected data on 105 women with BBD and 98 controls, focusing on their reproductive history and breast-feeding. We analysed data by R (version 2.12.1) considering p < 0.05 as significant. The results showed that fibroadenoma represented the most frequent BBD (55%), followed by fibrocystic changes (19%), intraductal papilloma (6%) and inflammatory breast disorders (5%). The mean age was 31.5 years (± 6.1), BMI 21.2 kg/m² (± 3.4) and age at menarche 13.0 years (± 1.5). Duration of breast-feeding was not significantly different between controls and BBD types (p = NS). Selecting women with fibroadenoma breast-feeding duration directly correlated with the number of benign lesions (p < 0.05), which remains significant also by multivariate analysis. It was concluded that there seemed to be no difference in breast-feeding among BBDs types, but lactation may influence the number of fibroadenomas. Moreover, prospective studies would better define the correlation between lactation and BBDs.

Risk factors for chronic pelvic pain in a cohort of primipara and secondipara at one year after delivery: association of chronic pelvic pain with autoimmune pathologies.

AIM: Over genetic and obsteteric factors, also autoimmunity may be involved in female chronic pelvic pain (CPP) pathogenesis. Our study aims to determinate the prevalence of CPP after one year from delivery, and to investigate the possible influence on CPP of concomitant autoimmune conditions. Methods. We selected a cohort of caucasian primipara and secondipara who delivered in our clinic in 2006. We collected personal, clinical and obstetric data, and asked them about pelviperineal painful symptoms. Results. Mean maternal age is 35.52 years (±4.70), 27.65% of women delivered by cesarean section, 61.04% spontaneously and 11.32% by operative assistance, with partoanalgesia in 10.39% of cases, episiotomy in 41.19%, vaginoperineal tears in respectively 14.10% I degree, 11.13% II degree and 0.93% III-IV degree; 43.60% of women have ever undergone abdominopelvic surgery, 32.84% by laparotomy-laparoscopy, 7.05% by hysteroscopy, 5.01% limited to perineum. Chronic autoimmune diseases affect 78.48% of women, allergies 7.79%, rheumatic pathologies 1.3%, autoimmune endocrinopathies 71.8%; 26.53% of women report pelviperineal painful symptoms, being already present in 2.23% of cases, 12.43% generalised pelvic pain, 4.27% bladder pain, 2.60% vulvodynia, 17. 07% dyspareunia. By monovariate analysis CPP results influenced by III-IV degree vaginoperineal tears, operative assistance, preexisting CPP, previous and actual urinary incontinence, previous abdominopelvic surgical interventions and chronic rheumatic pathologies. Furthermore, rheumatic disease, operative assistance and previous CPP are predictive factors for CPP in the postpartum (AUC=58.10%). Conclusion. Delivery may highlight CPP symptoms in predisposed women affected by chronic autoimmune pathologies.

Ultrasonographic assessment of cervix size and its correlation with female characteristics, pregnancy, BMI, and other anthropometric features.

PURPOSE: Cervical length during the first trimester of pregnancy has not been completely investigated yet. The objective of our study is to compare cervical size in the first ten gestational weeks with that of non-pregnant women, and to determine its correlation with maternal factors, including age, anthropometric features, and reproductive history. METHODS: We collected retrospective data about women who applied to the Obstetrics and Gynecology Outpatients Facility of Udine between February and June 2009, selecting both pregnant and non-pregnant women possessing a transvaginal ultrasonographic measurement of their cervix, and focusing on their age, parity, BMI, cervical, and uterine size. Data were analyzed by R (version.2.8.0), considering significant P < 0.05. RESULTS: 135 women were recruited. By multivariate linear regression, both cervical length and width result independently influenced by pregnancy status, and among non-pregnant nullipara, cervical length results to be significantly lower in women younger than 20 (P < 0.05). CONCLUSIONS: During the first ten gestational weeks, cervix results to be longer and wider than in non-pregnant women, suggesting the possible existence of early gestational, morphological, uterine, and cervical modifications. Women under the age of 20 have a significantly shorter cervix, suggesting an incomplete cervix maturity in this group of women, which may justify the higher prevalence of pre-term births in teenage pregnancies.

[Retrospective analysis of one year of cesarean sections: indications and risk factors associated with intrapartum cesarean section]. / Analisi retrospettiva su un anno di tagli cesarei: indicazioni e fattori di rischio per taglio cesareo in travaglio di parto.

AIM: Cesarean section (CS) is currently the most commonly performed surgical intervention worldwide. Indications include previous CS, podalic presentation and fetal macrosomia in antepartum CS, fetal distress, and prolonged first or second phase of labor in intrapartum CS. Despite the marked reduction in fetal mortality and morbidity in selected circumstances, maternal complication rates associated with CS are far higher than with vaginal delivery. The aim of this study was to evaluate the indications and maternal and fetal outcomes in a population undergoing antepartum or intrapartum CS and to analyze the risk factors of intrapartum CS. METHODS: An analysis was conducted on data from 1748 deliveries performed at the Gynecology-Obstetrics Clinic of the University of Udine during 2006. A total of 603 medical records of the mothers who had delivered by CS and their infants were analyzed. The Indications and maternal and fetal outcomes were evaluated in mothers who had undergone elective CS, emergency antepartum or intrapartum CS; multivariate analysis was then performed to define the risk factors associated with intrapartum CS. RESULTS: Cesarean sections accounted for 34.5% of all deliveries performed during 2006, of which 42.1% were elective CS, 21.1% emergency antepartum CS, and 36.8% intrapartum CS. The principal reason for CS delivery was previous CS in elective CS, gestational hypertension in emergency antepartum CS, and cardiotocographic alterations in emergency intrapartum CS. Multivariate logistic regression analysis showed that the independent risk factors for intrapartum CS were excessive weight gain during pregnancy and medically induced labor. CONCLUSION: A more accurate evaluation of the mother's and neonate's needs could help to improve the current rates of CS. This could be achieved by selection of cases in which there is a real need for CS and by acting on modifiable risk factors of intrapartum CS such as excessive weight gain during pregnancy.

[Outcome of pregnancy for immigrant women: a retrospective study]. / L'outcome della gravidanza nella donna immigrata: studio retrospettivo.

AIM: Italy is experiencing a continuous increase in female immigration and, as a consequence, the number of births by immigrant mothers. The objective of our study was therefore to compare indices for maternal-foetal wellbeing as regards immigrant as opposed to autochthonous pregnant women. METHODS: An analysis was made of CEDAP data from 2001 to 2008 concerning parturients at Udine Obstetric and Gynaecological Clinic, DRG clinical data for 2008 and clinical records for 2008 of foreign parturients: the focus was on which geographical area they came from, hypertensive and metabolic symptoms during pregnancy, maternal serology, gestational period up to childbirth, weight at birth, Apgar index, duration of hospitalisation for the mother and infant. RESULTS: The study covered 13,352 women of whom 2,139 were foreigners, while 363 of the latter gave birth in 2008. In terms of geographical area the largest group of immigrants came from Eastern Europe, followed by sub-Saharan African and Arab countries. The worst outcome of pregnancy was found in African women, who showed the highest incidence of chronic hypertension, pregnancy-induced hypertension and pre-eclampsia and they also developed gestational diabetes more frequently, although a high incidence was also seen for Eastern European and Arab women. Furthermore, African women were found to be HIV-seropositive more frequently, showed a greater tendency to preterm or severely preterm birth, with a significantly lower weight and Apgar at birth compared to all other immigrant women. As a result, African women and infants remained in hospital for a longer period. CONCLUSION: Monitoring, both pre-conceptional and during pregnancy, needs to be intensified, especially among African mothers, in order to reduce the maternal-foetal disadvantage when compared to other women.

[Prevalence of urinary incontinence and pelviperineal rehabilitation during the postpartum in a cohort of primipara and secondipara patients]. / Prevalenza dell'incontinenza urinaria e della riabilitazione pelvi-perineale nel postpartum in una coorte di pazienti primipare e secondipare.

AIM: Urinary incontinence is a classical sign of childbirth-related perineal trauma, the prevalence of which is estimated, depending on age, at between 10% and 50%. Pelviperineal rehabilitation offers an excellent opportunity to prevent pelviperineal disorders. The aim of the present study was to evaluate the prevalence of urinary incontinence and pelviperineal disorders in the local context, and also that of pelviperineal rehabilitation. METHODS: Of the 1793 women who gave birth in Udine in 2006, 900 primipara and secondipara Caucasians with single term pregnancies dated ultrasonically to be within 20 weeks of gestation, were selected. A total of 602 of them were contacted by telephone and two questionnaires were administered. RESULTS: The prevalence of pelviperineal rehabilitation in our population was 4.49%, while that of pelviperineal disorders was much higher, at around 40.20%. The prevalence of urinary incontinence was due in 27.57% of cases to stress and in 14.45% to urgency, with an overlap in 9.8% of cases and a story of prior incontinence in 9.97%. The prevalence of urinary urgency in women subjected to rehabilitation is significantly lower than in those not treated (P=0.004). Dyspareunia represents 16.11% of cases, coital incontinence 0.33%. One case of gas incontinence emerged but there was no case of faecal incontinence. CONCLUSIONS: Pelviperineal rehabilitation in the observed population has a very low prevalence, especially if compared with the high prevalence of disturbances related to dysfunctions of the pelvic floor during postpartum.

Summary of track D: social science: research, policy and action.

SCOPE: This review summarizes the main issues discussed during Track D, which examined the societal impact of HIV/AIDS, and responses to the epidemic by individuals, families, communities and societies worldwide. Micro- and macrolevel issues addressed included the development, implementation and evaluation of programmes for prevention and care; policy development and implementation; structural issues such as the impact of gender relations, development and migration on the development of the epidemic; and the social and economic impact of HIV/AIDS on affected societies and communities. RECURRENT THEMES: Presentations provided strong evidence that peer-led, community-based programmes offer particularly effective ways of working, and that participatory research involving affected communities provides useful results for the design and evaluation of programmes and policies. This is the case across settings, issues, populations and countries. FUTURE DIRECTIONS: Emerging needs include how best to ensure sustainability of national and international responses, how best to scale up successful interventions for wider reach, and how best to work with systematically marginalized, neglected groups and populations. Research priorities include the characterization of the multiple determinants of HIV-related vulnerability, and the evaluation of interventions that take these complex determinants as their starting point. A more coherent and strategic response requires less separation between the different constituencies involved in AIDS work, and the more sustained involvement of people living with HIV/AIDS themselves.

Assessing and alleviating the real impact of AIDS.

PIP: The impact of HIV/AIDS has been measured by calculating direct medical expenses and the indirect costs of lost production, which can be 10-20 times higher than the direct costs. Direct costs are hundreds of US dollars for low-income countries, thousands of dollars for middle-income countries, and tens of thousands of dollars for high-income countries such as Japan, Sweden, and the United States. Macroeconomic models have examined the effect of a shrinking labor force attributed to mortality from AIDS. In heavily affected Sub-Saharan countries economies will be impacted significantly, although this impact has not been proved yet. Beyond this measurable economic impact the devastating social and human cost is evident to the visitor in the Rakai region in Uganda, the Kagera in Tanzania, or the Cooperbelt in Zambia. It has been suggested that one major factor in the disintegration of Rwanda was the high HIV prevalence in the land. The severity of poverty also afflicts the infected, thus prevention measures could benefit mostly those with average income whose livelihood is disrupted by AIDS. Instead of focusing on the economic cost, the direct affect on people's lives should be measured. The benefits of health interventions are typically defined in terms of years of life gained and months of disability averted by expensive drugs and diagnostics. The relief of pain, nausea, and loneliness is mainly ignored. Pain control and support groups for people living with HIV/AIDS do not cost much in low-income countries where labor costs are also low. On the other hand, discrimination, stigmatization, and isolation cost more to maintain and perpetuate.^ieng

Adding the human dimension to economic analysis: why DALYs don't tell the whole story.

PIP: In order to best understand the impact of AIDS on a national level, it may be more important to understand its impact on the magnitude and severity of poverty than on national economic growth. It may also be true that the primary economic impact of AIDS is the concentrated breakdown of vulnerable structures such as the family, community, or even nations. The larger the structure, the more likely it can withstand collapse by distributing the impact, but vulnerability to collapse must be understood to avoid the catastrophe of breakdown. Rwanda may present the first example of the latter. Its AIDS prevalence was among the highest in the world, and the prevalence rate among members of the military was even higher. If studies consider the impact of HIV infection in terms of direct and indirect costs only, more dollars would be saved by preventing one case in the US than in most other countries. If, on the other hand, a hunger index is used (for each case of HIV how many people will go hungry and how many formerly hungry people will become malnourished), the greatest prevention benefit would probably occur in Uganda. In order to understand how economic factors fuel the epidemic and determine its impact, more socioeconomic data must be collected. When making the economic choices that maximize benefits to AIDS victims, the difficulty occurs in defining benefit. Most developing countries cannot provide the resources to prolong life and avert disability. However, there are ways to alleviate the impact of AIDS which all countries can afford: reducing pain, removing the barriers of discrimination, providing support groups, and helping people with the activities of daily life. In order to design the appropriate comprehensive care approaches in different settings, more data must be collected on how HIV-infected individuals perceive the impact of the disease on their lives.^ieng