Cadmium delays puberty onset and testis growth in adolescents.

OBJECTIVE: Cadmium (Cd) has been shown to impair pubertal development in experimental animals. However, no data are available for male adolescents with increased urinary cadmium levels. DESIGN: The aim of this cross-sectional study was to evaluate pubertal onset and pituitary-gonadal axis hormones in male adolescents with increased urinary levels of Cd. SUBJECTS: We studied 111 males, aged 12-14 years living in the Milazzo-Valle del Mela area. A control age-matched population (n = 60) living 28-45 km far from the industrial site was also enrolled. MEASUREMENTS: Pubertal stages were assessed by clinical examination according to Tanner's score. Mean testicular volume was also investigated by ultrasound examination. Urinary Cd concentration and blood levels of FSH, LH, testosterone and inhibin B were also investigated. RESULTS: Cd levels were significantly higher in adolescents living in the Milazzo-Valle del Mela area, compared to both age-matched subjects living far from the industrial plants and the reference values. Our population showed also a delayed onset of puberty, a smaller testicular volume and lower testosterone levels. An inverse correlation was found between urinary Cd and testicular volume (r = -0·25; P = 0·0008), testosterone levels (Spearman's r = -0·0·37; two-tailed P < 0·0001) and LH levels (Spearman's r = 0·048; P < 0·05). Testosterone levels were positively correlated with testicular volume (Spearman's r = 0·48; P < 0·0001). CONCLUSIONS: This study, for the first time, suggests that increased Cd burden is associated with delayed onset of puberty in male adolescents and impaired testicular growth.

Blockade of the JNK signalling as a rational therapeutic approach to modulate the early and late steps of the inflammatory cascade in polymicrobial sepsis.

Cecal ligation and puncture (CLP) is an experimental polymicrobial sepsis induced systemic inflammation that leads to acute organ failure. Aim of our study was to evaluate the effects of SP600125, a specific c-Jun NH2-terminal kinase (JNK) inhibitor, to modulate the early and late steps of the inflammatory cascade in a murine model of CLP-induced sepsis. CB57BL/6J mice were subjected to CLP or sham operation. Animals were randomized to receive either SP600125 (15 mg/kg) or its vehicle intraperitoneally 1 hour after surgery and repeat treatment every 24 hours. To evaluate survival, a group of animals was monitored every 24 hours for 120 hours. Two other animals were sacrificed 4 or 18 hours after surgical procedures; lung and liver samples were collected for biomolecular and histopathologic analysis. The expression of p-JNK, p-ERK, TNF-α, HMGB-1, NF-κB, Ras, Rho, Caspase 3, Bcl-2, and Bax was evaluated in lung and liver samples; SP600125 improved survival, reduced CLP induced activation of JNK, NF-κB, TNF-α, and HMGB-1, inhibited proapoptotic pathway, preserved Bcl-2 expression, and reduced histologic damage in both lung and liver of septic mice. SP600125 protects against CLP induced sepsis by blocking JNK signalling; therefore, it can be considered a therapeutic approach in human sepsis.

Flavocoxid, a nutraceutical approach to blunt inflammatory conditions.

Flavonoids, from Scutellaria baicalensis (Chinese skullcap) and Acacia catechu (black catechu), have been shown to exert a variety of therapeutic effects, including anti-inflammatory, antiviral, antibacterial, and anticancer activities. Flavocoxid is a mixed extract containing baicalin and catechin and it acts as a dual balanced inhibitor of cyclooxygenase-1 (COX-1) and COX-2 peroxidase enzyme activities with a significant inhibition of 5-lipoxygenase (5-LOX) enzyme activity in vitro. Flavocoxid downregulates gene or protein expression of several inflammatory markers and exerts also strong antioxidant activity in several experimental models. Controlled clinical trials and a postmarketing study have clearly shown that flavocoxid is as effective as naproxen in managing the signs and symptoms of osteoarthritis of the knee and it has better upper gastrointestinal, renal, and respiratory safety profile than naproxen. Flavocoxid may therefore provide a potential therapeutic approach to the treatment of chronic inflammatory conditions.

A 7-Years Active Pharmacovigilance Study of Adverse Drug Reactions Causing Children Admission to a Pediatric Emergency Department in Sicily.

Children represent one of the most susceptible groups to adverse drug reactions (ADRs), as a consequence of physiological growth and maturation of different organ systems. The aim of this study was to characterize the frequency, preventability and seriousness of ADRs recorded in the Pediatric Emergency Department (ED) of the University hospital of Messina, in Sicily. All the suspected adverse reactions to drugs and vaccines collected from 2012 to 2018 were selected and then analyzed. Only adverse drug reactions (ADRs) with a probable or possible causality assessment were included, according to the Naranjo Algorithm and the World Health Organization criteria; the preventability assessment using Schumock and Thornton criteria was also carried out. The Medical Dictionary for Regulatory Activities (MedDRA) was used to group ADRs. Of 75,935 admissions to the Pediatric ED, 120 were due to suspected ADRs. The rate of hospital admission due to ADRs (75.8%) was significantly greater than that of patients without ADRs (11.9%). Among pediatric patients with ADRs the median (Q1-Q3) age was 29.5 (12-73.25) months. Most of ADRs were observed in infants and children (43.3% and 41.7%, respectively vs adolescents, 15%). In addition, in children with ADRs, females [41 (14-105)] were older than males [23 (11-45)] (p=0.044). Most adverse reactions were serious (75.8%) and 20.8% were preventable or probably preventable; however, the majority of serious ADRs (93.4%) resulted without sequelae. The reactions were found to be as probable (54.2%) or possible (45.8%). Vaccines (n=63), antibacterials (n=31) and anti-inflammatory medicines (n=14) were the most frequently drugs involved. Organ toxicity mapping due to vaccines was general disorders and administration site conditions (65.1%), nervous disorders (50.2%), cutaneous disorders (35%), followed by gastrointestinal disorders (20.6%). Cutaneous disorders (76%) gastrointestinal (20.7%), general (15.5%), and nervous disorders (8.6%) were the organ toxicity mapping due to drugs. Active pharmacovigilance has an essential role in supporting the development of strategies aimed at intervention to reduce admissions due to ADRs. Our data suggest that ADRs represent the first cause of hospitalization to the Pediatric Emergency Department. Furthermore, according to the literature, vaccines and antibiotics are the most frequent cause of adverse drug reactions in children.

Anti-obesity drug therapy in clinical practice: Evidence of a poor prescriptive attitude.

Obesity is a worldwide growing problem for the health care systems and its treatment is strongly recommended. Orlistat, naltrexone/bupropion, and liraglutide are approved for weight loss in Italy in patients with a Body Mass Index (BMI) ≥ 30 kg/m2 or ≥ 27 kg/m2 with concomitant diseases. However, the prescription of these drugs is significantly low worldwide. General practitioners (GPs) play a key role in the early diagnosis and appropriate management of obesity. The aim of the study was to investigate the management of obesity and the prescriptive attitude of anti-obesity drugs in a general practice setting. All patients registered in lists of 8 GPs with a recorded diagnosis of obesity or BMI values ≥ 30 kg/m2 in the period 2017-2018, were recruited. A descriptive analysis of demographic and clinical characteristic was carried out. The Spearman's correlation rank test was applied to identify correlations between BMI and all the variables of interest. Among 1301 obese patients, only 66.1 % had been diagnosed and 29.4 % had no registered BMI value. Patients with recorded BMI, were overweight (7.8 %) or in the obesity class I (38.8 %), class II (14.1 %), and class III (7.1 %), respectively. The obese patients (class 1-3) were older [66 (55-76) vs 49 (32-59); p < 0.01], and had more concurrent diseases [5 (3-8) vs 4 (2-6); p < 0.01] than patients who reached a BMI < 30 Kg/m2. Moreover, most of obese were high cardiovascular risk (HCVr) patients (67.0 % vs 31.9 %; p < 0.01). The BMI was directly related to age (rs 0.14; p < 0.01), diabetes (rs 0.19; p < 0.01), hypertension (rs 0.14; p < 0.01), heart failure (rs 0.09; p < 0.01), HCVr (rs 0. 12; p < 0.01) and number of comorbidities (rs 0.08; p = 0.01). No prescriptions of orlistat or naltrexone/bupropion were found. Liraglutide was prescribed only in 7 patients because of the concomitant presence of diabetes. Our results suggest a low adherence to guide line recommendations for obesity management and confirm an under-prescription of anti-obesity drugs in Italy.

Flavocoxid Protects Against Cadmium-Induced Disruption of the Blood­Testis Barrier and Improves Testicular Damage and Germ Cell Impairment in Mice [corrected].

Cadmium (Cd) causes male infertility. There is the need to identify safe treatments counteracting this toxicity. Flavocoxid is a flavonoid that induces a balanced inhibition of cyclooxygenase (COX)-1 and COX-2 peroxidase moieties and of 5-lipoxygenase (LOX) and has efficacy in the male genitourinary system. We investigated flavocoxid effects on Cd-induced testicular toxicity in mice. Swiss mice were divided into 4 groups: 2 control groups received 0.9% NaCl (vehicle; 1 ml/kg/day) or flavocoxid (20 mg/kg/day ip); 2 groups were challenged with cadmium chloride (CdCl2; 2 mg/kg/day ip) and administered with vehicle or flavocoxid. The treatment lasted for 1 or 2 weeks. The testes were processed for biochemical and morphological studies. CdCl2 increased phosphorylated extracellular signal-regulated kinase (p-ERK) 1/2, tumor necrosis factor (TNF)-α, COX-2, 5-LOX, malondialdehyde (MDA), B-cell-lymphoma (Bcl)-2-associated X protein (Bax), follicle-stimulating hormone (FSH), luteinizing hormone (LH), transforming growth factor (TGF) -ß3, decreased Bcl-2, testosterone, inhibin-B, occludin, N-Cadherin, induced structural damages in the testis and disrupted the blood-testis barrier. Many TUNEL-positive germ cells and changes in claudin-11, occludin, and N-cadherin localization were present. Flavocoxid administration reduced, in a time-dependent way, p-ERK 1/2, TNF-α, COX-2, 5-LOX, MDA, Bax, FSH, LH, TGF-ß3, augmented Bcl-2, testosterone, inhibin B, occludin, N-Cadherin, and improved the structural organization of the testis and the blood-testis barrier. Few TUNEL-positive germ cells were present and a morphological retrieval of the intercellular junctions was observed. In conclusion, flavocoxid has a protective anti-inflammatory, antioxidant, and antiapoptotic function against Cd-induced toxicity in mice testis. We suggest that flavocoxid may play a relevant positive role against environmental levels of Cd, otherwise deleterious to gametogenesis and tubular integrity.

Oxidative stress and DNA repair and detoxification gene expression in adolescents exposed to heavy metals living in the Milazzo-Valle del Mela area (Sicily, Italy).

BACKGROUND: The area of Milazzo-Valle del Mela (Sicily, Italy) is considered at high risk of environmental crisis by regional authorities. OBJECTIVE: To measure oxidative-stress, DNA repair and detoxification genes in school children living near the industrial area and in age-matched controls. METHODS: The parent study was a biomonitoring investigation evaluating heavy metal urine levels in 226 children aged 12-14 years, living in the high risk area, and in 29 age-matched controls living 45 km far from the industrial site. In the present study 67 exposed adolescents and 29 controls were included. Samples were analyzed for urinary 8-hydroxydeoxyguanosine (8OHdG) levels, and gene expression of OGG1 (DNA repair gene), NQO1, ST13, and MT1A (detoxifying genes). RESULTS: Urinary cadmium was higher (p = 0.0004) in exposed [geometric mean, 0.46 µg/L; 25th-75th percentile: 0.3-0.56] than in control adolescents [geometric mean, 0.26 µg/L; 25th-75th percentile: 0.2-0.3]. Chromium was also significantly elevated in exposed [geometric mean, 1.52 µg/L; 25th-75th percentile: 1.19-1.93] compared with controls [geometric mean, 1.25 µg/L; 25th-75th percentile: 1.05-1.48; p = 0.02]. Urinary 8-OHdG concentration was greater in exposed than in controls (71.49 vs 61.87 µg/L, p = 0.02), and it was correlated with cadmium levels (r = 0.46, p < 0.0001), and with the combined exposure index (r = 0.43, p < 0.0001). Moreover, cadmium levels showed a robust correlation with OGG1 and MT1A gene expression levels (r = 0.44, p < 0.0001; r = 0.39, p < 0.0001, respectively). Finally, OGG1 and MT1A were over-expressed in adolescents from Milazzo-Valle del Mela area compared with controls (p = 0.0004; p < 0.0001, respectively). CONCLUSIONS: Continuous exposure at relatively low concentrations of heavy metals is associated with increased oxidative DNA damage and impaired expression of DNA repair and detoxification genes in adolescents.

Levels of heavy metals in adolescents living in the industrialised area of Milazzo-Valle del Mela (northern Sicily).

In the Milazzo-Valle del Mela area, the presence of industrial plants and the oil refinery make local residents concerned for their health. For this reason, we evaluated the levels of heavy metals in 226 children aged 12-14 years, living in the 7 municipalities of the area. A control age-matched population (n = 29) living 45 km far from the industrial site was also enrolled. Arsenic, cadmium, chromium, mercury, nickel, and vanadium were analysed in 24 h urine samples, while lead concentration was evaluated in blood samples. A questionnaire regarding life style and risk perception was also administered. Adolescents from Milazzo-Valle del Mela had cadmium levels significantly higher compared to either controls (P < 0.0001) or the reference values of the European Germany Environmental Survey (GerES-IV) and the American National Health and Nutrition Examination Survey (NHANES). Furthermore, children had higher perception of living in a high-risk environment. The present data, for the first time, clearly indicate that adolescents living in Milazzo-Valle del Mela have increased body concentration of cadmium, which may be harmful to human health. These results deserve particular attention by the local and regional government to initiate prevention programmes in this susceptible population.