Medullary Sponge Kidney and Urinary Calculi Aeromedical Concerns

Medullary Sponge Kidney (MSK) is a benign disorder associated with renal stones in 60% of patients. Patients frequently have episodic painless hematuria but are otherwise asymptomatic unless renal calculi or infections complicate the disease. Nephrolithiasis is a relative, but frequently enforced, contraindication to space or other high performance flight. Two case reports of asymptomatic NASA flight crew with MSK and three cases of military aviators diagnosed with MSK are reviewed, all cases resulted in waiver and return to flight status after treatment and a vigorous follow up and prophylaxis protocol. MSK in aviation and space flight necessitates a highly case-by-case dependent evaluation and treatment process to rule out other potential confounding factors that might also contribute to stone formation and in order to re-qualify the aviator for flight duties

Synthesis, structural characterisation and biological studies of new mononuclear platinum(II) complexes with sterically hindered heterocyclic ligands

Three novel cisplatin analogues were synthesized, designed according to an approach which violates the ‘‘classical’’ structure–activity relationship, by replacing the diamine ligands with a planar N donor heterocycle giving a sterically hindered complex. Moreover, the sterical hindrance of antitumor drug candidates potentially makes them less susceptible to deactivation by sulphur-containing proteins and helping to overcome resistance mechanisms. The resulting mononuclear complexes of sterically hindered polidentate heterocyclic N ligands [PtCl(bbp)]Cl (1) [bbp = 2,6-bis(2-benzimidazolyl)pyridine], [PtCl2(dptdn)](H2O) (2) [dptdn = sodium 5,6-diphenyl-3-(20-pyridyl)-1,2,4-triazine-400,400 0-disulfonate] and [(dptdn)(dpt)Pt]Cl2(H2O) (3) [dpt = 5,6-diphenyl-3-(20-pyridyl)-1,2,4-triazine] have been prepared and structurally characterised. Both neutral and ionic complexes are present, with monofunctional (1) and bifunctional Pt(II) moieties (2) and coordinatively saturated Pt(II) ions in the mixed ligand complex (3), whose size and shape enable them to behave as novel scaffolds for DNA binding. All complexes were tested ‘‘in vitro’’ for their biological activity on human HT29 colorectal carcinoma and HepG2 hepatoma cells. The complexes (1) and (3), endowed with a positive charge, showed a potent cytotoxic activity and reduced cell viability with an efficacy higher than that of cisplatin; whilst the neutral bifunctional compound (2) was inactive. IC50 values have been calculated for the active compounds. The cytotoxic effects were confirmed by the accumulation of treated cells in subG0/G1 phase of cell cycle, by the loss of mitochondrial potential (Dwm) and by the chromatin condensation or fragmentation observed by means of fluorescence microscopy after Hoechst 33258 nuclear staining. A study on intracellular platinum uptake in HT29 cell line has been also performed and data obtained strongly suggest that the cytotoxicity of new tested complexes reported in this work is based on a different pharmacodynamic pattern with respect to cisplatin

Trial sequential meta-analysis of laparoscopic versus open pancreaticoduodenectomy: is it the time to stop the randomization?

Background: The advantages of LPD compared with OPD remain debatable. The study aimed to compare the laparoscopic (LPD) versus open (OPD) for pancreaticoduodenectomy. Methods: A meta-analysis of randomized studies (RCTs) comparing LPD and OPD was made. The results were reported as relative risk (RRs) or mean differences (MDs). The trial sequential analysis was used to test the type I and type II errors defining the required information size (RIS). The primary outcome was mortality, major morbidity, and postoperative pancreatic fistula (POPF). R1 resection, post-pancreatectomy hemorrhage, delayed gastric emptying, biliary fistula, reoperation, readmission, operative time (OT), lymph nodes harvested, and length of stay (LOS) were also studied. Results: Four RCTs, counting 818 patients, were found. The RRs for mortality, major morbidity, and POPF were 1.16, 1.04, and 0.86, without significant differences. The RISs were 35,672, 16,548, and 8206. To confirm this equivalence, at least 34,854, 15,730, and 7338 should be randomized. OT was significantly longer in LPD than OPD, with an MD of 63.22. The LOS was significantly shorter in LPD than in OPD, with − 1.76 days. The RISs were 1297 and 1273, excluding a false-positive result. No significant differences were observed for the remaining endpoints, and RISs suggested that more than 3000 patients should be randomized to confirm the equivalence. Conclusion: The equivalence of LPD and OPD for mortality, major morbidity, and POPF is affected by type II error. The RISs to demonstrate a superiority of one of the two techniques seem unrealistic to obtain

Induced pluripotent stem cells for therapy personalization in pediatric patients: Focus on drug-induced adverse events

Adverse drug reactions (ADRs) are major clinical problems, particularly in special populations such as pediatric patients. Indeed, ADRs may be caused by a plethora of different drugs leading, in some cases, to hospitalization, disability or even death. In addition, pediatric patients may respond differently to drugs with respect to adults and may be prone to developing different kinds of ADRs, leading, in some cases, to more severe consequences. To improve the comprehension, and thus the prevention, of ADRs, the set-up of sensitive and personalized assays is urgently needed. Important progress is represented by the possibility of setting up groundbreaking patient-specific assays. This goal has been powerfully achieved using induced pluripotent stem cells (iPSCs). Due to their genetic and physiological species-specific differences and their ability to be differentiated ideally into all tissues of the human body, this model may be accurate in predicting drug toxicity, especially when this toxicity is related to individual genetic differences. This review is an up-to-date summary of the employment of iPSCs as a model to study ADRs, with particular attention to drugs used in the pediatric field. We especially focused on the intestinal, hepatic, pancreatic, renal, cardiac, and neuronal levels, also discussing progress in organoids creation. The latter are three-dimensional in vitro culture systems derived from pluripotent or adult stem cells simulating the architecture and functionality of native organs such as the intestine, liver, pancreas, kidney, heart, and brain. Based on the existing knowledge, these models are powerful and promising tools in multiple clinical applications including toxicity screening, disease modeling, personalized and regenerative medicine

The non-euphoric phytocannabinoid cannabidivarin counteracts intestinal inflammation in mice and cytokine expression in biopsies from UC pediatric patients

Patients with ulcerative colitis (UC) using marijuana have been reported to experience symptomatic benefit. Cannabidivarin (CBDV) is a safe non-psychoactive phytocannabinoid able to activate and desensitize TRPA1, a member of the TRP channels superfamily, which plays a pivotal role in intestinal inflammation. Here, we have investigated the potential intestinal anti-inflammatory effect of CBDV in mice and in biopsies from pediatric patients with active UC. Colonic inflammation was induced in mice by dinitrobenzenesulfonic acid (DNBS). The effect of orally administered CBDV on macroscopic and microscopic damage, inflammatory parameters (i.e. myeloperoxidase activity, intestinal permeability and cytokine production) and faecal microbiota composition, was evaluated 3 days after DNBS administration. TRPA1 expression was studied by RT-PCR in inflamed colons of mice as well as in mucosal colonic biopsies of children with active UC, whose response to incubation with CBDV was also investigated. CBDV attenuates, in a TRPA1-antagonist sensitive manner, DNBS-induced signs of inflammation including neutrophil infiltration, intestinal permeability, and cytokine (i.e. IL-1\u3b2, IL-6 and the chemokine MCP-1) production. CBDV also alters the dysregulation of gut microbiota associated to colitis. Finally, CBDV lessens cytokine expression in colonic biopsies from pediatric patients with ulcerative colitis, a condition in which TRPA1 was up-regulated. Our preclinical study shows that CBDV exerts intestinal anti-inflammatory effects in mice via TRPA1, and in children with active UC. Since CBDV has a favorable safety profile in humans, it may be considered for possible clinical trials in patients with UC

Summary of the fourth international workshop on deep learning for testing and testing for deep learning (DeepTest 2023)

Deep Learning (DL) techniques help software developers thanks to their ability to learn from historical information which is useful in several program analysis and testing tasks (e.g., malware detection, fuzz testing, bug-finding, and type-checking). DL-based software systems are also increasingly adopted in safety-critical domains, such as autonomous driving, medical diagnosis, and aircraft collision avoidance systems. In particular, testing the correctness and reliability of DL-based systems is paramount, since a failure of such systems would cause a significant safety risk for the involved people and/or environment. The 4th International Workshop on Deep Learning for Testing and Testing for Deep Learning (DeepTest 2023) was co-located with the 45th International Conference on Software Engineering (ICSE), with the goal of targeting research at the intersection of software engineering and deep learning and devise novel approaches and tools to ensure the interpretability and dependability of software systems that depends on DL components