RAGE inhibition blunts insulin-induced oncogenic signals in breast cancer.

The receptor for advanced glycation end products (RAGE) is implicated in diabetes and obesity complications, as well as in breast cancer (BC). Herein, we evaluated whether RAGE contributes to the oncogenic actions of Insulin, which plays a key role in BC progression particularly in obese and diabetic patients. Analysis of the publicly available METABRIC study, which collects gene expression and clinical data from a large cohort (n = 1904) of BC patients, revealed that RAGE and the Insulin Receptor (IR) are co-expressed and associated with negative prognostic parameters. In MCF-7, ZR75 and 4T1 BC cells, as well as in patient-derived Cancer-Associated Fibroblasts, the pharmacological inhibition of RAGE as well as its genetic depletion interfered with Insulin-induced activation of the oncogenic pathway IR/IRS1/AKT/CD1. Mechanistically, IR and RAGE directly interacted upon Insulin stimulation, as shown by in situ proximity ligation assays and coimmunoprecipitation studies. Of note, RAGE inhibition halted the activation of both IR and insulin like growth factor 1 receptor (IGF-1R), as demonstrated in MCF-7 cells KO for the IR and the IGF-1R gene via CRISPR-cas9 technology. An unbiased label-free proteomic analysis uncovered proteins and predicted pathways affected by RAGE inhibition in Insulin-stimulated BC cells. Biologically, RAGE inhibition reduced cell proliferation, migration, and patient-derived mammosphere formation triggered by Insulin. In vivo, the pharmacological inhibition of RAGE halted Insulin-induced tumor growth, without affecting blood glucose homeostasis. Together, our findings suggest that targeting RAGE may represent an appealing opportunity to blunt Insulin-induced oncogenic signaling in BC.

A simple method to equalize the workload when operating several small wastewater treatment plants: a case study.

The aim of the present study is to define a simple (and easy to use) method to equalize the workload of personnel operating several small wastewater treatment plants (SWWTPs). The approach is illustrated through a case study which is the result of collaboration between researchers and a water and wastewater management company operating in Southern Italy. The topic is important since personnel have a significant impact on the operating costs of SWWTPs, and the approach outlined results in the minimum number of staff being required to assure the management of the service. Four kinds of work units are considered: plant managers, assistant plant managers, laboratory technicians and executives. In order to develop a practical, feasible and easy to use method, the workload was evaluated considering only the population equivalent (PE) and the number of plants managed. The core of the method is the evaluation of the percentage of time that the personnel units devote to the operation of SWWTPs of the municipality considered. The proposed procedure offers a useful tool to equalize the workload, both in terms of PE and the number of plants managed, the procedure being easily modifiable to introduce other evaluation criteria. By using familiar concepts such as PE and number of plants managed, the approach of the method can easily be understood by management. It can also be readily adapted to other similar situations.

A comparison of the efficacy of organic and mixed-organic polymers with polyaluminium chloride in chemically assisted primary sedimentation (CAPS).

CAPS is the acronym for chemically assisted primary sedimentation, which consists of adding chemicals to raw urban wastewater to increase the efficacy of coagulation, flocculation and sedimentation. The principal benefits of CAPS are: upgrading of urban wastewater treatment plants; increasing efficacy of primary sedimentation; and the major production of energy from the anaerobic digestion of primary sludge. Metal coagulants are usually used because they are both effective and cheap, but they can cause damage to the biological processes of anaerobic digestion. Generally, biodegradable compounds do not have these drawbacks, but they are comparatively more expensive. Both metal coagulants and biodegradable compounds have preferential and penalizing properties in terms of CAPS application. The problem can be solved by means of a multi-criteria analysis. For this purpose, a series of tests was performed in order to compare the efficacy of several organic and mixed-organic polymers with that of polyaluminium chloride (PACl) under specific conditions. The multi-criteria analysis was carried out coupling the simple additive weighting method with the paired comparison technique as a tool to evaluate the criteria priorities. Five criteria with the following priorities were used: chemical oxygen demand (COD) removal > turbidity, SV60 > coagulant dose, and coagulant cost. The PACl was the best alternative in 70% of the cases. The CAPS process using PACl made it possible to obtain an average COD removal of 68% compared with 38% obtained, on average, with natural sedimentation and 61% obtained, on average, with the best PACl alternatives (cationic polyacrylamide, natural cationic polymer, dicyandiamide resin).

Groundwater recharge in an endoreic basin with reclaimed municipal wastewater.

The aim of this paper was to evaluate the groundwater pollution in an endoreic basin in southern Italy. The aquifer circulation was carried out on two different levels: a shallow groundwater, with a water table of about 10 m, and a deep groundwater in a karst aquifer, with a water table of 140-190 m. Reclaimed municipal wastewater and superficial water collected in the catchment area were both drained in a swallow hole linked with the deep groundwater. The agricultural practice conducted in the endoreic basin produced an excess of nitrate in the soil. Nitrate was subsequently washed out and displaced in the groundwater. With regard to the EU Drinking Water Directive (98/83/EC), the research activity conducted during 2003 showed the absence of pollution in the deep groundwater used for drinking water supply. The shallow groundwater, instead, was strongly influenced by agricultural and pasture activities, with detectable levels of nitrates and bacteria. In order to reduce the load of pollution entering the swallow hole and then in the deep groundwater, the realisation of a constructed wetland plant was proposed to improve the quality of reclaimed wastewater, as well as to pursue the wastewater reuse in agriculture.

Effects of two diet techniques and delivery mode on weight loss, metabolic profile and food intake of obese adolescents: a fixed diet plan and a calorie-counting diet.

The aim of this study is to compare the weight loss of obese adolescents on two different low-calorie diets: fixed diet plan and calorie-counting diet. This is a randomized clinical study with 66 obese adolescents (body mass index Z score (ZBMI)>+3, 13.7±0.7 years, 60.6% male) with anthropometric, food intake, physical activity, laboratory, body composition and stage of pubertal development data evaluated. There was a reduction in the ZBMI in both groups (P<0.0001), without significant difference between them (P=0.87). There was a significant reduction in insulin, and homeostasis model assessment insulin resistance (HOMA-IR), with no difference between groups. A reduction in total energy intake of the groups was found, with an increase in the proportion of protein and reduction in carbohydrates. In this cohort of severely obese adolescents, fixed diet plan and calorie-counting diet led to a similar reduction of ZBMI, metabolic markers and total energy intake.

Blockade of central and peripheral luteinizing hormone-releasing hormone (LHRH) receptors in neonatal rats with a potent LHRH-antagonist inhibits the morphofunctional development of the thymus and maturation of the cell-mediated and humoral immune responses.

The development of the thymus and the hypothalamic-pituitary-gonadal axis are linked by bidirectional hormonally mediated relationships. In the present study, the direct involvement of the neuropeptide LHRH in the maturation of the thymus and development of the cell-mediated and humoral immune responses were assessed after treatment of neonatal (from post-natal day 1-day 5) female rats with a potent LHRH-antagonist (LHRH-anta, p-Glu-D-Phe 2.6,Pro3-LHRH, 50 micrograms/rat), and the effects compared to those resulting from neonatal castration. Whereas in control animals the maturation of mitogenic potential in thymocyte cultures showed a progressive and age-dependent increase, reaching a maximal activity at 30 days of age and then decreasing after puberty onset, in LHRH-anta-treated rats, the thymocyte's proliferative response was completely blocked at 7 days of age and remained very low at each time interval studied, until 3 months of age. A similar effect of the LHRH-anta treatment on splenocyte cultures was measured. Moreover, a reduced percentage of the T-helper lymphocyte subpopulation followed LHRH-anta administration. By contrast, in neonatally castrated rats, blastogenic activity was significantly higher, compared to control cultures, at each stage studied. Treatment with LHRH-anta produced a significant decrease in thymus wt, an alteration of the maturational pattern characterized by a cellular monomorphism, reduced thymocyte volume, reduction of the cortical area, and depauperation of the epithelial microenvironment. Moreover, a morphometric analysis revealed a selective decrease in the large lymphoid cell population of the subcapsular cortex at 7 and 15 days. On the other hand, neonatal castration produced an opposite effect, leading to a marked hypertrophy of the cortical area, and counteracted the post-puberal thymus atrophy. When LHRH-anta-treated adult (3-month-old) rats were challenged with an antigenic stimulus (multiple sc injections of complete Freund adjuvant and BSA) and antibody (anti-BSA antibodies of the immunoglobulin G class) production measured in the serum after 15 days, a marked and significant decrease in immunoglobulin G levels was observed, compared to the values measured in untreated control. The described immune deficiencies in LHRH-anta-treated rats were associated with a clear inhibition of sexual maturation. This study clearly indicates that the blockade of central and peripheral LHRH receptors during a critical period for maturation of both hypothalamus-hypophyseal-gonadal axis and brain-thymus-lymphoid axis dramatically impairs immune system development, suggesting a potential role of the neuropeptide LHRH in the bidirectional programming of both neuroendocrine and immune functions.

Hypertension in a group of centenarians.

The aim of the present study was to evaluate the frequency of hypertension in a group of extremely old persons: 73 centenarians resident in Calabria were studied, aged 100-110 years, (mean age 102.95 +/- 2.0), 54 women (73.9%) and 19 men (26.1%), in the period January 1st and April 30th, 1994. All the centenarians were visited at their homes. Hypertensive centenarians were 14 (19.1%), women 12 (85.7%) and men 2 (14.3%). Even if blood pressure progressively increases with age, we have not found it in centenarians. The lesser frequency of hypertension in centenarians certainly depends on genetic and constitutional factors, but also their way of life and alimentary habits (decreased sodium intake, increase of calcium and potassium intake), as we have proven in a recent work, could be determinant. Moreover, the presence of hypertensive centenarians might mean that hypertension does not prevent to reach an age by far above the average, if it is the only risk factor.

Multidimensional evaluation in a group of centenarians.

A group of 40 Calabrian centenarians (12 males, 28 females) was studied from June 1 to December 31, 1993. Their age was ranging from 100 to 107 years (mean age: 102.3 +/- 1.8 years). Clinical evaluation was performed by recording anamnestic data, an objective examination, and by assessing cognitive performance, emotional and nutritional status, as well as functional activity. The following tests were applied: mini mental state examination (MMSE), geriatric depression scale (CDS), activity of daily living (ADL), and instrumental activity of daily living (IADL). The nutritional status was estimated by collecting answers to a questionnaire regarding nutritional habits and by measuring body weight, height and calculating body mass index (BMI). In assessment of the socio-economic conditions, the following parameters were considered: years of education, type of job, type of residence ownership, heating system used, toilet set available and the regular income. Our multidimensional evaluation has revealed, in agreement with other findings, that the Calabrian centenarians seem to be a selected population with an amazingly high activity, who overcame severe age-dependent diseases, probably because of their genetic pattern and of the environmental factors which may favor longevity.

[Appendiceal mucoceles. A case report]. / Il mucocele appendicolare. Analisi di un caso.

A case of benign mucocele presenting as a subocclusive syndrome is reported; the surgical treatment consisted in a right colectomy. Appendiceal mucoceles are rare lesions of the appendix, characterized by a gross enlargement of the appendix from accumulation of mucoid substance within the lumen. It is a rare condition, encountered in only 0.1-0.4% of all appendectomies with a female predominance and an average age at the time of diagnosis over 50 years. Following careful review of the literature, the difficulties in differential diagnosis are underlined, especially between benign and malignant forms and the possibility of a pre-operative diagnosis is examined. Abdominal ultrasound and CT scan of the abdomen or colonoscopy may suggest the diagnosis. However, often the diagnosis is an incidental event. The pathogenesis, histologic aspect of the lesion and the different surgical strategies are discussed. A frozen section examination should be performed in all patients, while the abdomen is open, because it may be impossible to predict the underlying pathology merely by inspecting the serosal surface of a dilated appendix. If a simple retentional cyst is uncovered, without atypia, appendectomy should be curative; if cystadenoma or cystadenocarcinoma of the appendix are found, more extended resection was necessary. However if the operation is done as an emergency, a frozen section examination is not always available: in those patients a more extended resection is suggested.

[Skin metastasis from renal carcinoma: epidemiologic and clinical features]. / Metastasi cutanee da carcinoma renale: aspetti epidemiologici e clinici.

The Authors present an additional case of a 70-years old male patient with skin metastasis from renal cell carcinoma, 15 months after nephrectomy. The patient died ten months later for advanced neoplastic disease. Skin metastasis affect 3-6% of patients with renal cell carcinoma. The surgical treatment is mandatory for single nodule. Chemotherapy is often ineffectual. The prognosis is poor, with a 0-8% 5-years survival for patients with multiple nodules.

[A case of breast metastasis in bladder urothelioma]. / Su di un caso di metastasi mammaria da urotelioma vescicale.

A case of isolated mammary metastasis from surgically untreated urothelial vesical carcinoma is discussed. An integrated chemo-radiotherapeutical treatment had been planned, due to bad general condition; after this, an optimal subjective benefit and good objective response (reduction in lesion diameter < 50%, MR) were obtained. An isolated breast lesion appeared ten months after; its metastatic nature was only indirectly suspected by mammographic and echographic features. Only immunohistochemical study, realized on percutaneous needle biopsy specimen, definitively confirmed the urothelial metastatic origin. In present work, biological and prognostic significance of mammary metastases and the needing of distinguishing them from primary breast neoplasm are analysed, basing on the literature review.

[Malignant mesothelioma located in the pleura: its radical surgical treatment]. / Il mesotelioma maligno localizzato della pleura: trattamento chirurgico radicale.

The authors report a rare case of localized malignant pleural mesothelioma infiltrating the thoracic wall. The absence of widespread pleural involvement allowed for a radical operation with removal of a large portion of the thoracic wall. However, due to rarity of such tumor, an hypothesis on long term prognosis is difficult to formulate.

Prenatal and postnatal findings of acrania.

INTRODUCTION: Acrania is a rare congenital anomaly in which the flat bones of the cranial vault are partial or complete absent with complete but abnormal development of the cerebral hemispheres. CASE REPORT: We report two cases, diagnosed prenatally by ultrasound and followed by medical pregnancy termination, one with isolated acrania and one with associated cleft lip and palate and spina bifida. DISCUSSION: The acrania pathogenesis is unknown and differential diagnosis should be made with other conditions like anencephaly and acalvaria. Genetic counselling is not easy because there is no evidence for a specific genetic origin, but the extreme rarity and sporadic nature suggests a low recurrence risk.

Prenatal diagnosis of congenital diaphragmatic hernia in a McFadden Kalousek type 2 triploid fetus.

Triploidy is characterized by an extra haploid set. We report a rare case of a prenatally diagnosed digynic type (McFadden/Kalousek type 2) triploid fetus with congenital diaphragmatic hernia (CDH). Prenatal ultrasonographic examination allows reliable detection of CDH and it is therefore of great importance for proper parental counselling, as well as performing fetal karyotype for associated chromosomal anomalies.

Ultrasonographic examination of the uterine cervix is better than cervical digital examination as a predictor of the likelihood of premature delivery in patients with preterm labor and intact membranes.

OBJECTIVE: The purpose of this study was to compare the diagnostic performance of ultrasonographic and digital examination of the cervix in the prediction of preterm delivery in patients presenting with preterm labor and intact membranes. STUDY DESIGN: Endovaginal ultrasonography was performed in 59 patients admitted with preterm labor (20 to 35 weeks) and cervical dilatation of < 3 cm. Cervical parameters evaluated included endocervical length, the presence of funneling, funnel length, funnel width, cervical index ([Funnel length + 1]/Endocervical length), and cervical dilatation and effacement as determined by digital examination. Outcome variables were the occurrence of preterm delivery (< 36 weeks) and the admission-to-delivery interval. RESULTS: The prevalence of preterm delivery was 37.3% (22/59). Receiver-operator characteristic curve and logistic regression analyses indicated a significant relationship between the occurrence of preterm delivery and ultrasonographic cervical parameters (p < 0.005 for each) but not with the results of digital examination of the cervix. Survival analysis demonstrated a shorter admission-to-delivery interval for patients with an abnormal cervical index or endocervical length (p < 0.005 for each). CONCLUSIONS: Endovaginal ultrasonographic examination of the uterine cervix is more accurate than digital examination of the cervix in the assessment of the risk for preterm delivery in patients with preterm labor and intact membranes.

The value of amniotic fluid interleukin-6, white blood cell count, and gram stain in the diagnosis of microbial invasion of the amniotic cavity in patients at term.

PROBLEM: Subclinical microbial invasion of the amniotic cavity occurs in 18.8% of women with term labor and intact membranes and in 34% of patients with term PROM and is a risk factor for the development of puerperal infection related morbidity. Although amniotic fluid white blood cell count, interleukin-6 determination, and Gram stain examination have been used for the diagnosis of intrauterine infection in patients with preterm labor and preterm premature rupture of membranes, no information is available about the accuracy and specific cut-off values for these tests in patients at term. The purpose of this study was to compare the performance of the amniotic fluid Gram stain examination, white blood cell count, and interleukin-6 determination in the identification of microbial invasion of the amniotic cavity in patients at term with and without PROM. METHOD: Amniotic fluid was retrieved from 148 patients with term gestations (90 patients with spontaneous labor and intact membranes and 58 patients with PROM). Samples were cultured for bacteria and Mycoplasma species. Amniotic fluid Gram stain, white blood cell count, and interleukin-6 determinations (ELISA, sensitivity: 43 pg/ml) were performed in all samples. Microbial invasion of the amniotic cavity was defined as a positive amniotic fluid culture for microorganisms. Analysis was conducted using Mann-Whitney U test, Fisher's exact test, receiver operating characteristic curves and logistic regression. RESULTS: Patients with spontaneous labor and intact membranes: The prevalence of microbial invasion of amniotic cavity in this group was 15.6% (14/90). The most sensitive test for the detection of microbial invasion of the amniotic cavity was amniotic fluid interleukin-6 determination (sensitivity for: interleukin-6 > or = 5.7 ng/ml = 86%, white blood cell count > or = 20 cells/mm3 = 64%, Gram stain = 28%). The most specific test was the Gram stain of the amniotic fluid (specificity for: Gram stain = 84%, interleukin-6 = 79% and white blood cell count = 63%). Multiple logistic regression demonstrated that amniotic fluid interleukin-6 concentration was the only covariate that retained statistical significance when intrauterine infection was used as outcome variable. Patients with PROM: The prevalence of a positive amniotic fluid culture in this group was 39.7% (23/58). Logistic regression demonstrated that only interleukin-6 retained a significant relationship with the results of amniotic culture when all variables were entered simultaneously into a model to predict amniotic fluid culture results. The most sensitive tests for the detection of intrauterine infection were interleukin-6 determination and white blood cell count (sensitivity for interleukin-6 > or = 3.4 ng/ml and white blood cell count > or = 20 cells/mm3 = 69.6% for both). The most specific test was Gram stain (97.1%). CONCLUSIONS: Amniotic fluid interleukin-6 determination is the best rapid test for the detection of microbial invasion of the amniotic cavity in patients at term with and without PROM. When this test is not available, amniotic fluid Gram stain and white blood cell count represent valid diagnostic tools to assess the microbial state of amniotic cavity.

The use of GnRH agonists depot for the treatment of dysfunctional uterine bleeding.

The Authors report their experience with the use of GnRH analogue (Goserelin) in 35 women with abnormal uterine bleeding due to low-risk hyperplasia of the endometrium. A hysteroscopic and histopathological follow-up was performed at 2 months and 6 months after treatment. The results show a significantly effectiveness of Goserelin in treating dysfunctional uterine bleeding.

[Male breast cancer. Histochemical and flow cytometry analysis of 6 cases]. / Carcinoma mammario maschile. Analisi immunoistochimica e citofluorimetrica di 6 casi.

The authors studied immunohistochemical and flow cytometric parameters of 6 male breast carcinomas. All patients were ER positive and frequency of aneuplody was 66%. Diploid tumors showed low proliferative activity and S-phase fraction < 3%.