Search

Our previous studies exploring melphalan resistance in the human rhabdomyosarcoma xenograft TE-671 MR revealed elevation of DNA polymerase-alpha and DNA polymerase-beta. The present study evaluated the alteration of melphalan activity in TE-671 (melphalan-sensitive) and TE-671 MR (melphalan-resistant) subcutaneous xenografts in nude mice after DNA polymerase-alpha was inhibited using aphidicolin glycinate (AG) and DNA polymerase-beta was inhibited using dideoxycytidine (DDC). Administration of AG or DDC did not produce toxicity or demonstrate antineoplastic activity when given alone. AG (90 mg/m2) enhanced the activity of melphalan against TE-671, with growth delays increasing by 8.4, 15.8, and 21.2 days over the regimen with melphalan only. AG (180 mg/m2) only modestly increased melphalan activity against TE-671 MR, with the growth delays increasing from 9.6 and 12.1 days using melphalan alone to 12.1 and 14.5 days using melphalan plus AG. AG (180 mg/m2) plus melphalan (the dose lethal to 10% of animals) produced greater weight loss compared with melphalan alone, whereas DDC plus melphalan produced no additional toxicity. DDC modestly enhanced the activity of melphalan plus AG against TE-671 MR. AG plus O6-benzylguanine did not increase the activity of 1,3-bis(2-chloroethyl)-1-nitrosourea against TE-671 or TE-671 MR. AG (90 mg/m2 and 180 mg/m2) inhibited DNA polymerase-alpha to 80% and 72% of control in TE-671 and 64% and 37% in TE-671 MR, and DDC inhibited DNA polymerase-beta to 59% in TE-671 and 48% in TE-671 MR. These results suggest a role for AG-mediated enhancement of melphalan activity, particularly in the treatment of newly diagnosed, melphalan-sensitive tumors. [ABSTRACT FROM AUTHOR]

Islet transplantation constitutes a major leap in the treatment of type 1 diabetes. The inflammatory response triggered by the intra portal infusion of islet appears possibly deletary for islet implantation and transplantation outcome. In this study scientists explored the factors potentially involved in this reaction, focusing on the tissue factor (TF) because of its importance in the coagulation pathway and in the inflammatory reaction. Using RT-PCR and immunochemistry, scientists screened for tissue factor in normal pancreata and in isolated pancreatic tissue. Scientists then measured tissue factor activity in apparend endocrine, exocrine and non-purified isolated cells using an amidolytic method. Scientists also studied several markers of coagulation and inflammation during 7 consecutives human islet allotransplantations. The degree of activation was then correlated to the various biological and physical characteristics of the preparations infused, in particular their TF content.

The SARS-CoV-2 pandemic has impacted our lives since early 2020. Both malnutrition and an overweight status significantly correlate with worse patient outcomes and mortality. Immuno-nutrition (IN) has shown promising results in the inflammatory bowel disease (IBD) clinical course and the extubation time and mortality of patients admitted to intensive care units (ICUs). Thus, we wanted to assess the impact of a standardized IN oral formula on COVID-19 patients admitted to our mild-intensity clinic in late 2021. We prospectively enrolled patients admitted to the Internal Medicine COVID-19 Unit of San Benedetto General Hospital. All patients had biochemical, anthropometric, HRCT chest scan, and nutritional assessments at the time of admission and, after oral immuno-nutrition formula administration, at 15 days of the interval follow up. We enrolled 52 consecutive patients (mean age of 60.9 ± 5.4 years, 17 F, and BMI of 23.5 Kg/m 2 ). The main comorbidities were diabetes (20%, type 2: 90%), hyperuricemia (15%), hypertension (38%), chronic ischemic heart disease (12%), COPD (13%), anxiety (10%), and depression (8%). Upon informed consent, 14 patients (mean age of 67.9 ± 5.4 years, 7 F, and BMI of 26.7 Kg/m 2 ) were accepted to be administered IN. A moderate to severe overweight status was present in 59% of the patients; MNA test (4.4 ± 0.7) and phase angle (PA) values, suggestive of malnutrition, were present in 13% of the patients. After 15 days of admission, we recorded three deaths (mean age of 68.9 ± 4.1 years, 3 F, and BMI of 27.5 Kg/m 2 ). An overweight status significantly correlated with the exitus occurrence (r = 0.65). One death was reported among the IN-treated patients. IN administration was followed by a significant decrease in inflammatory markers with a tendency to be higher than those of non-treated patients. IN prevented the worsening of BMI and PA vs. non-treated patients. In this overweight COVID-19 population, immuno-nutrition prevented malnutrition development with a significant decrease in inflammatory markers.

This study aimed to evaluate the postsurgical effects from 5 years on the palate after surgical repair of the lip at 3 or 9 months of age in children with cleft lip and palate. Eighty-four digitized dental impressions were divided into the following groups: group 1 (G1): lip surgery at 3 months of life; group 2 (G2): lip surgery at 9 months of life; group 3 (G3): without orofacial cleft. Five angular (C'IC, ICM, IC'M', CMM', and C'M'M) and 3 linear parameters (C-C', c-c', and M-M') were evaluated. Statistical analysis was applied with α=5%. Intraclass Correlation Coefficient was significantly smaller in G1 than in G3 ( P =0.005), while IC'M' was significantly smaller in G3 than in G1 ( P <0.001). C'M'M was significantly smaller in G1 than in G2 and G3 ( P <0.001). The distances C-C' and c-c' were significantly smaller in G1 than in G2 and G3 ( P <0.001). There was a statistically significant difference in both G1 and G2 ( P <0.001, in all) in the analysis of palatal symmetry. Linear regression analysis showed that the, 11.2% of outcomes determined by c-c' distance can be explained by the age of lip repair ( P =0.013). In conclusion, lip surgery at 3 months of life showed a tendency toward more restriction in 5-year postsurgery palate development. The age of cheiloplasty is one of the factors that can influence palatal development; however, other factors may be associated and should be studied., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by Mutaz B. Habal, MD.)

Objective: The aim of this study was to evaluate the microvasculature of the macula and the optic nerve in patients affected by migraine with aura (MA) and without aura (MO) by optical coherence tomography angiography (OCTA), comparing the findings with healthy controls (HC)., Methods: We collected data from ocular and orthotic examinations, including eye motility, intraocular pressure measurement, best-corrected visual acuity (BCVA) measurement, objective refraction measurement, fundus examination, macular and optic disk OCTA examination. All subjects were imaged with solix fullrange OCT. The following OCTA parameters were recorded: macular vessel density (VD), inside disc VD, peripapillary VD, disc whole image VD, fovea choriocapillaris VD, fovea VD, parafovea VD, peripapillary thickness, fovea thickness, parafovea thickness, macular full retinal thickness, and foveal avascular zone (FAZ) parameters. Clinical and demographical data about migraine patients were collected by a neurologist., Results: We included 56 eyes from 28 patients with a diagnosis of MO, 32 eyes from 16 patients with a diagnosis of MA, and 32 eyes from 16 HC subjects. The FAZ area was 0.230 ± 0.099 mm 2 in the MO group, 0.248 ± 0.091 mm 2 in the MA group and 0.184 ± 0.061 mm 2 in the control group. The FAZ area was significantly larger in the MA group than in the HC group (p = 0.007). The foveal choriocapillaris VD was significantly lower in MA patients (63.6 ± 2.49%) when compared with MO patients (65.27 ± 3.29%) (p = 0.02)., Conclusion: An impairment of retinal microcirculation can be detected in patients with MA, as demonstrated by the enlargement of FAZ. Moreover, the study of choroid circulation may reveal microvascular damage in patients with migraine with aura. OCTA is a useful non-invasive screening tool for the detection of microcirculatory disturbance in patients with migraine., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: COVID-19 has hit every country in the world. Almost a quarter of a billion cases and nearly 5 million deaths reported globally as of late September 2021. Compared to over 6 billion doses of COVID-19 vaccine administered, the pandemic does not seem to disappear. The duration of protective immunity is currently not defined. Primary immune responses are inevitably declining and the continuous transmission of increasingly worrying viral variants., Objective: The primary objective of the study is to evaluate the antibody response at 120 and 180 days in employees of an hospital of Marche (Italy) who have completed the vaccination cycle with Pzifer-Biontech vaccine and to highlight the correlation with quantitative and qualitative variables. The secondary objective is to study the nature and frequency of adverse events in relation to variables such as comorbidity, age, gender, working areas and developed antibody titer., Materials and Methods: An observational retrospective study was carried out to evaluate the antibody response at 120 and 180 days. Subjects receiving a double dose of vaccine at least 21 days apart and those receiving the second dose of the same vaccine between 18 January 2021 and 31 March 2021 shall be considered. The study included non-probability sampling of convenience. All parties have provided informed written consent to access personal and clinical data., Results: The sample is composed by 1.115 subjects. The results of the study reveal an important immune response detected by IgG dosage, both at 120 and 180 days after the second dose of Sars-Cov-2 vaccine mRNA BNT162b2 vaccine (Pzifer-Biontech), other than very rare exceptions. Antibody values are higher among hospital workers compared to those working in other areas, both 120 and 180 days. These values are even higher in the health professionals who provide assistance in wards with positive Covid patients, both at 120 days (p=0.06) and at 180 days; the mean values of IgG are statistically higher in direct assistance of Covid patients at 180 days(p=0.029). The most frequent adverse drug events after the second dose of vaccine were pain at the site of inoculation of the vaccine (70.7%), fatigue (35%) and arthralgia (19%). It was finally shown that people with diabetes or smokers had an average antibody response statistically lower than 120 days and 180 days from the second dose., Discussion and Conclusion: This study leads to the conclusion that the second dose of vaccine Sars-Cov-2 vaccine mRNA BNT162b2 vaccine allows a consistent antibody response. Further multicentric studies are needed to investigate the antibody response to vaccination Sars-Cov-2 mRNA BNT162b2.

Background: The pandemic and its related social restrictions have led to many uncertainties in nurse education, including the fear of infection in clinical learning settings and the challenge of remote learning. The modification of clinical and academic environments generated anxiety and academic concerns among nursing students., Objectives: To explore the main determinants of anxiety related to the clinical and classroom environments in nurse education after the second wave of the COVID-19 Pandemic., Design: Multicentre cross-sectional study., Settings: Ten universities offering nursing bachelor programs in central and southern Italy., Participants: A convenience sample of 842 nursing students., Methods: From April to July 2021, the Self-Rating Anxiety Scale and the Altered Student Study Environment Tool were administered to assess, respectively, students' anxiety and their concerns about the study environment. A regression model was tested., Results: Most of the nursing students were female (76.6 %), living with family (70.9 %), and full-time students (85.7 %); 44.6 % were third-year of Bachelor in Nursing students. The majority of the participants (88.5 %) showed a level of anxiety. The statistically significant predictors of anxiety levels were concerns about grade attainment (β=0.42, p < 0.001) in the total sample, and, among the first-year students, the completion of clinical placement (β=0.14, p = 0.047)., Conclusions: Results suggest a need for the redesign of teaching activities and clinical learning experiences to ensure academic outcomes and to preserve students' psychological well-being. Models of learning environments' dynamic adaptation and ongoing psychological support should be implemented to develop tailored interventions., Competing Interests: Declaration of competing interest The authors have no conflict of interests to declare., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Children undergoing surgery generally experience anxiety during the perioperative period, which could impact the surgical outcome, cause long-term psychological consequences and result in later healthcare avoidance. Preoperative anxiety in children is managed using both pharmacological and non-pharmacological therapies. The latter include distraction, a tour of the operating room and parental presence until the induction of anaesthesia. A novel and effective non-pharmacological therapies is the use of virtual reality to reduce anxiety and pain in children scheduled for medical procedures. However, the effectiveness of virtual reality in paediatric surgery has yet to be evaluated in a systematic review., Objective: To evaluate the effectiveness of virtual reality in the management of anxiety in paediatric patients during the perioperative period., Design: Both a systematic review and a meta-analysis of randomised controlled trials were performed according to the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions Section 8.5 and in accordance with the Cochrane Effective Practice and Organisation of Care. The results are reported as prescribed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist., Data Sources: A systematic search of randomised controlled trials was conducted using Medline, SCOPUS, Web of Science, Ovid MEDLINE and CINAHL., Review Methods: Two researchers screened potentially eligible articles and then assessed the quality of the reported studies using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions Section 8.5 and according to Cochrane Effective Practice and Organisation of Care. The data were synthesised using the random-effects models to incorporate the estimated heterogeneity in the weighting. Heterogeneity was tested using the Q and I 2 statistics. The τ 2 statistic, an estimate of the amount of variation between the included studies, was also determined. Studies whose heterogeneity with respect to primary outcome measurements hindered pooling of the results for meta-analysis were summarised narratively., Results: Seven studies were eligible for inclusion in this systematic review. An effect size for anxiety could be determined in six. The results support the effectiveness of virtual reality in reducing anxiety in paediatric patients undergoing elective surgery. The overall effect was supported by a confidence interval < 0 (PL = -0.341, 95% confidence interval: -0.620 to -0.107) and by heterogenity indexes that were non significant (Q = 9.49, p = 0.091) or not important (I 2  = 38.64%)., Conclusions: Paediatric patients undergoing elective surgery may benefit from virtual reality as a distraction method that can reduce anxiety. PROSPERO register, number: (blinded for Referee)., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aims: To investigate which morality traits are more important for nurses to determine positive opinions of their nurse manager., Background: People selected morality more often than sociability and competence when forming a positive opinion towards an ideal or a newcomer manager., Methods: A multicentre, cross-sectional study was carried out by administering two questionnaires to 775 nurses on the influence of morality, sociability and competence traits on their impression formation processes., Results: Regarding nurses' perceptions about the morality, sociability and competence traits of an ideal nurse manager, the total score for morality was 20.0; for sociability, it was 14.2; and for competence, it was 19.6. For nurses' opinions about a new nurse manager, the total score of the morality section was 16.2, which was very similar to the total score of the competence section (mean = 16.1)., Conclusion: Morality positively influences nurses' initial impression of an ideal manager, and though it seems to be a necessary condition, it is not sufficient by itself to support the nursing staff's perception towards a new manager., Implications for Nursing Management: Our findings could be useful in better understanding the role of morality in social perceptions and behavioural consequences of staff nurses towards their nurse manager., (© 2021 John Wiley & Sons Ltd.)

Background: Pedicled perforator flaps can present postoperative complications similar to those encountered in free flap surgery. Beyond a clinical evaluation, there is still no reliable technical aid for the early prediction of vascular issues. The aim of this study was to assess the support of near-infrared spectroscopy technology as an intraoperative tool to anticipate postsurgical flap ischemia., Methods: We prospectively enrolled 13 consecutive patients who were referred to our hospital from March 2017 to July 2018 and required a reconstructive procedure with a pedicled fasciocutaneous perforator flap. We measured flap peripheral capillary oxygen saturation (SpO2) in each patient with a Somanetics INVOS 5100C Cerebral/Somatic Oximeter (Medtronic), both before and after transposition. Patient demographics, operative data, and complications were then recorded during the following 6 months. We analyzed the data using the Wilcoxon signed-rank test and linear regression., Results: The mean flap SpO2 before and after transposition was 92%±3% and 78%±19%, respectively. The mean change in SpO2 was 14%±17%, with a range of 0% to 55%. The change in saturation and mean saturation ratio were significantly different between patients with and without postoperative flap necrosis., Conclusions: An immediate quantitative analysis of flap peripheral capillary SpO2 after transposition has never before been described. In our experience, an intraoperative drop in SpO2 equal to or greater than 15%-20% predicted vascular complications in pedicled perforator flaps. Conversely, flap size and rotation angle were not correlated with the risk of flap necrosis.

The experience of working on the frontlines of the COVID-19 healthcare crisis has presented a cumulative traumatic experience that affects healthcare professionals' well-being. Psychological resources such as resilience and adaptive defense mechanisms are essential in protecting individuals from severe stress and burnout. During September 2020, 233 healthcare workers responded to an online survey to test the impact of demographic variables, COVID-19 exposure, and psychological resources in determining stress and burnout during the COVID-19 emergency. Frontline workers reported higher scores for stress, emotional exhaustion, and depersonalization ( p < 0.001) as compared to colleagues working in units not directly serving patients with COVID-19. Mature defensive functioning was associated with resilience and personal accomplishment ( r = 0.320; p < 0.001), while neurotic and immature defenses were related to perceived stress and burnout. Stress and burnout were predicted by lower age, female gender, greater exposure to COVID-19, lower resilience, and immature defensive functioning among healthcare professionals (R 2 = 463; p < 0.001). Working on the frontlines of the COVID-19 pandemic appears to provoke greater stress and burnout. On the other hand, resilience and adaptive defense mechanisms predicted better adjustment. Future reaction plans should promote effective programs offering support for healthcare workers who provide direct care to patients with COVID-19.

In mammals, free d-aspartate (D-Asp) is abundant in the embryonic brain, while levels remain very low during adulthood as a result of the postnatal expression and activity of the catabolizing enzyme d-aspartate oxidase (DDO). Previous studies have shown that long-lasting exposure to nonphysiological, higher D-Asp concentrations in Ddo knockout (Ddo -/- ) mice elicits a precocious decay of synaptic plasticity and cognitive functions, along with a dramatic age-dependent expression of active caspase 3, associated with increased cell death in different brain regions, including hippocampus, prefrontal cortex, and substantia nigra pars compacta. Here, we investigate the yet unclear molecular and cellular events associated with the exposure of abnormally high D-Asp concentrations in cortical primary neurons and in the brain of Ddo -/- mice. For the first time, our in vitro findings document that D-Asp induces in a time-, dose-, and NMDA receptor-dependent manner alterations in JNK and Tau phosphorylation levels, associated with pronounced cell death in primary cortical neurons. Moreover, observations obtained in Ddo -/- animals confirmed that high in vivo levels of D-Asp altered cortical JNK signaling, Tau phosphorylation and enhanced protein SUMOylation, indicating a robust indirect role of DDO activity in regulating these biochemical NMDA receptor-related processes. Finally, no gross modifications in D-Asp concentrations and DDO mRNA expression were detected in the cortex of patients with Alzheimer's disease when compared to age-matched healthy controls., (Copyright © 2019. Published by Elsevier Inc.)

The neuronal loss caused by excessive glutamate release, or 'excitotoxicity', leads to several pathological conditions, including cerebral ischemia, epilepsy, and neurodegenerative diseases. Over-stimulation of presynaptic N-methyl-D-aspartate (NMDA) receptors is known to trigger and support glutamate spillover, while postsynaptic NMDA receptors are responsible for the subsequent apoptotic cascade. Almost all molecules developed so far are unable to selectively block presynaptic or postsynaptic NMDA receptors, therefore a deeper knowledge about intracellular NMDA pathways is required to design more specific inhibitors. Our previous work showed that presynaptic c-Jun N-terminal kinase 2 (JNK2) specifically regulates NMDA-evoked glutamate release and here we demonstrate that an interaction between Syntaxin-1a and JNK2 is fundamental to this mechanism. Based on this evidence, a new cell permeable peptide (CPP), "JGRi1", has been developed to disrupt the JNK2/STX1a interaction to indirectly, but specifically, inhibit presynaptic NMDA receptor signaling. JGRi1 reduces the NMDA-evoked release of glutamate both in in-vitro and ex-vivo experiments while also being able to widely diffuse throughout brain tissue via intraperitoneal administration. In conclusion, the JNK2/STX1 interaction is involved in presynaptic NMDA-evoked glutamate release and the novel CPP, JGRi1, acts as a pharmacological tool that promotes neuroprotection.