Synthesis and characterisation of a new benzamide-containing nitrobenzoxadiazole as a GSTP1-1 inhibitor endowed with high stability to metabolic hydrolysis

The antitumor agent 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (1) is a potent inhibitor of GSTP1-1, a glutathione S-transferase capable of inhibiting apoptosis by binding to JNK1 and TRAF2. We recently demonstrated that, unlike its parent compound, the benzoyl ester of 1 (compound 3) exhibits negligible reactivity towards GSH, and has a different mode of interaction with GSTP1-1. Unfortunately, 3 is susceptible to rapid metabolic hydrolysis. In an effort to improve the metabolic stability of 3, its ester group has been replaced by an amide, leading to N-(6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexyl)benzamide (4). Unlike 3, compound 4 was stable to human liver microsomal carboxylesterases, but retained the ability to disrupt the interaction between GSTP1-1 and TRAF2 regardless of GSH levels. Moreover, 4 exhibited both a higher stability in the presence of GSH and a greater cytotoxicity towards cultured A375 melanoma cells, in comparison with 1 and its analog 2. These findings suggest that 4 deserves further preclinical testing

Letrozole versus Clomiphene for Infertility in the Polycystic Ovary Syndrome

BACKGROUND Clomiphene is the current first-line infertility treatment in women with the polycystic ovary syndrome, but aromatase inhibitors, including letrozole, might result in better pregnancy outcomes. Full Text of Background... METHODS In this double-blind, multicenter trial, we randomly assigned 750 women, in a 1:1 ratio, to receive letrozole or clomiphene for up to five treatment cycles, with visits to determine ovulation and pregnancy, followed by tracking of pregnancies. The polycystic ovary syndrome was defined according to modified Rotterdam criteria (anovulation with either hyperandrogenism or polycystic ovaries). Participants were 18 to 40 years of age, had at least one patent fallopian tube and a normal uterine cavity, and had a male partner with a sperm concentration of at least 14 million per milliliter; the women and their partners agreed to have regular intercourse with the intent of conception during the study. The primary outcome was live birth during the treatment period. Full Text of Methods... RESULTS Women who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P=0.007; rate ratio for live birth, 1.44; 95% confidence interval, 1.10 to 1.87) without significant differences in overall congenital anomalies, though there were four major congenital anomalies in the letrozole group versus one in the clomiphene group (P=0.65). The cumulative ovulation rate was higher with letrozole than with clomiphene (834 of 1352 treatment cycles [61.7%] vs. 688 of 1425 treatment cycles [48.3%], P Full Text of Results... CONCLUSIONS As compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00719186.

The impact of intra-operative factors in otosclerosis outcomes: retrospective study in a tertiary centre

The aim of the study was to assess results from a large cohort of patients undergoing otosclerosis surgery with respect to the impact of intra-operative variables on post-operative hearing function and complications. We enrolled 384 patients affected by otosclerosis who were subjected to stapes surgery between 2004 and 2013 at a single institution. Surgery was performed in all cases under local anaesthesia, using a manual perforator and/or microdrill. Teflon-piston prosthesis was used in all patients. Audiological data obtained preoperatively and at last follow-up examination (minimum 12 months) were compared. Statistical analysis was performed using the multiple regression model. Peripheral rim otosclerosis and diffuse otosclerosis were associated with better functional results compared to the obliterative pattern (p < 0.05). Mean post-operative Air-Bone Gap was significantly higher in the 0.4 mm, compared to 0.6 mm piston group at 0.5 kHz (p < 0.001) and 1 kHz (p < 0.02); in the stapedotomy group a statistically significant difference was found between 0.4 and 0.6 mm piston groups, in favour of the latter (p < 0.05). No differences were encountered in terms of average hearing threshold and complications. Intra-operative variables cannot be fully predictable and our data could help in stratification of the results and as a landmark for the surgeon’s decisions

Surgical multidisciplinary approach of orbital complications of sinonasal inflammatory disorders

Orbital infection complicating sinonasal inflammatory disorders may lead to serious sequelae, including blindness and death, if untreated. Communication between the otorhinolaryngologist, neuroradiologist, ophtalmologist, neurosurgeon and maxillo-facial surgeon is critical and time-sensitive for a successful treatment. The large majority of pre-septal cellulitis cases resolves after broad-spectrum antibiotic therapy. Also orbital cellulitis has been found responsive to pharmacological approach in most cases. The management of the subperiosteal abscess (SPA) is more controversial. An aggressive surgical approach is always recommended also in case of cavernous sinus thrombosis. In cases of surgical indication, debate is still open on the timing and the approach (endoscopic or external). The surgeon should be prepared to convert an endoscopic approach to an external one if needed and this should be included in the informed consent. Decompression of one or more orbital walls may be necessary if orbital pressure remains elevated. Immediate surgery is indicated in children with large SPA or orbital abscesses (OA), or in immune-compromised patients. Moreover, any worsening in the ophthalmological function must be carefully considered as a landmark in candidacy to surgery

Psychological Determinants of Consumer Acceptance of Personalised Nutrition in 9 European Countries

YesObjective: To develop a model of the psychological factors which predict people’s intention to adopt personalised nutrition. Potential determinants of adoption included perceived risk and benefit, perceived self-efficacy, internal locus of control and health commitment. Methods: A questionnaire, developed from exploratory study data and the existing theoretical literature, and including validated psychological scales was administered to N = 9381 participants from 9 European countries (Germany, Greece, Ireland, Poland, Portugal, Spain, the Netherlands, the UK, and Norway). Results: Structural equation modelling indicated that the greater participants’ perceived benefits to be associated with personalised nutrition, the more positive their attitudes were towards personalised nutrition, and the greater their intention to adopt it. Higher levels of nutrition self-efficacy were related to more positive attitudes towards, and a greater expressed intention to adopt, personalised nutrition. Other constructs positively impacting attitudes towards personalised nutrition included more positive perceptions of the efficacy of regulatory control to protect consumers (e.g. in relation to personal data protection), higher self-reported internal health locus of control, and health commitment. Although higher perceived risk had a negative relationship with attitude and an inverse relationship with perceived benefit, its effects on attitude and intention to adopt personalised nutrition was less influential than perceived benefit. The model was stable across the different European countries, suggesting that psychological factors determining adoption of personalised nutrition have generic applicability across different European countries. Conclusion: The results suggest that transparent provision of information about potential benefits, and protection of consumers’ personal data is important for adoption, delivery of public health benefits, and commercialisation of personalised nutrition.This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement n u 265494 (http://cordis.europa.eu/fp7/home_en.html). Food4Me is the acronym of the project ‘‘Personalised nutrition: an integrated analysis of opportunities and challenges’’ (http://www.food4me.org/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Classical vs. Retrograde Endoscopic Dacryocystorhinostomy: Analyses and Comparison of the Results

Background: In endoscopic dacryocystorhinostomy (DCR), surgical landmarks such as the maxillary line (ML) and the axilla of the middle turbinate (MT) guide the surgeon in identifying the lacrimal sac. The primary surgical risk associated with the classical technique, which involves directly opening the lacrimal sac, is the height of the bone drilling on the projection of the lateral wall of the nasal fossa. This poses a significant risk of damaging the orbit, the floor of the frontal sinus, and the anterior skull base. Furthermore, the anatomical variability in size and location of the lacrimal sac poses a risk for difficult and precise surgical identification. Recently, a ‘retrograde’ technique has been introduced to safely identify and expose the lacrimal sac. The aim of this study is to compare the results of retrograde DCR (rDCR) to a classic technique (clDCR), in terms of clinical recurrence and complications. Methods: A retrospective study on a cohort of 35 patients who underwent DCR at the ENT Department of the Modena University Hospital between January 2010 and October 2022 (18 clDCR and 17 rDCR) was performed. Minimum postoperative follow-up for inclusion was 12 months. We used the Fisher’s exact test to compare the two techniques, comparing functional outcomes and clinical recurrence rates. Results: Clinical recurrence of nasolacrimal stenosis in clDCR patients was 50%, compared to 6% in those who underwent rDCR (p-value 0.005). Postoperative surgical complications were not significantly different between the two groups (p > 0.05). Conclusions: rDCR is a safe technique and has been shown to be a statistically more effective surgical technique than clDCR in reducing clinical recurrence rates

SARS-CoV-2 tracheitis in laryngectomised patients: A consecutive case-series study

Key points SARS-CoV-2 is a possible cause of acute severe tracheitis in laryngectomees. In our series, the clinical picture was characterized by a haemorrhagic tracheitis with a slow resolution pattern. We observed a histological pattern of erosive inflammation of the respiratory epithelium. Planned tracheo-bronchoscopy and tracheal toilettes are recommended to prevent critical obstruction of the airway, which can be fatal in patients with associated impairment of lung function caused by SARS-CoV-2 infection. The present cases highlight the need for close interdisciplinary working and communication in the management of airway complications of COVID-19 infection

The cadaveric studies and the definition of the antero-lateral ligament of the knee: From the anatomical features to the patient-specific reconstruction surgical techniques

Cadaver studies represented a milestone in surgical orthopaedic research, and still today they play a crucial role in the achievement of new knowledge about joint disease behaviour and treatment. In this review, an overview of the cadaver studies available in the literature about the anatomy, role, and treatment of the antero-lateral ligament (ALL) of the knee was performed. The aim of the review was to describe and gain more insight into the part of in vitro study in understanding knee joint anatomy and biomechanics, and in developing surgical reconstruction techniques. The findings of the review showed that cadaver studies had, and will continue to have, a key role in the research of knee joint biomechanics and surgical reconstruction. Moreover, they represent a powerful tool to develop and test new devices which could be useful in clinical and surgical practice

Histopathological growth patterns of neuroendocrine tumor liver metastases

Histopathological growth patterns (HGPs) of liver metastases represent a potential biomarker for prognosis after resection. They have never been studied in neuroendocrine tumor liver metastases (NETLM). This study evaluated if distinct HGPs can be observed in resected NETLM and if they have prognostic value. Sixty-three patients who underwent resection of NETLM between 01–01-2001 and 31–12-2021 were retrospectively included. HGPs were scored on Haematoxylin&amp;Eosin slides using light microscopy, distinguishing desmoplastic- (dHGP), pushing- (pHGP) and replacement HGP (rHGP). Average HGP scores were calculated per patient. Each patient was classified according to predominant HGP. Overall and Disease-Free Survival (OS and DFS) were evaluated through Kaplan–Meier analysis and Cox regression. Eighteen patients had predominant dHGP (29%), 33 had predominant pHGP (52%) and 11 had predominant rHGP (17%). One patient had mixed HGP (2%). Five-year OS was 76% (95%CI: 66–87%) for the overall cohort. Five-year OS was 92% (95%CI: 77–100%) for dHGP, was 73% (95%CI: 59–91%) for pHGP, 50% (95%CI: 25–100%) for rHGP. Five-year DFS was 39% (95%CI: 19–83%) for dHGP, 44% (95%CI: 27–71%) for rHGP and 50% (95%CI: 23–100%) for pHGP. There was no significant association between HGP and OS or DFS in multivariable analysis. Distinct HGPs could be identified in NETLM. In patients who underwent resection of NETLM, no association was found between HGPs and postoperative survival. Half of the patients with NETLM have a predominant pushing growth pattern, which is a rare growth pattern in liver metastases from breast and colorectal cancer.</p