In multimorbid, unvaccinated and non-hospitalized patients, early administration of remdesivir, nirmatrelvir/ritonavir and molnupiravir was effective in reducing the risk of hospitalization or death ...from any cause. Similar data are lacking with regard to patients already hospitalized and who acquire in-hospital SARS-CoV-2 infection. We conducted a retrospective study during two outbreaks of SARS-CoV-2 infections involving 90 inpatients already hospitalized for medical or surgical conditions, in order to assess the effectiveness of early administration of remdesivir. Forty-seven cases were treated with a 3-day course of remdesivir (200 mg on day 1 and 100 mg on days 2 and 3) within a median time of 1.4 day from testing positive, and were compared to a matched case-control cohort of 43 untreated patients; matching was based on age, sex, vaccination status, previous symptomatic infections by SARS-CoV-2, reasons for hospitalization (no significant differences). No case presented adverse events to remdesivir or death from COVID-19. No significant difference in overall in-hospital mortality was observed in cases compared to controls (17% vs 16.3%, p=0.925), but progression to severe pneumonia, although the difference was still not significant, showed an evident trend of a better outcome (8.5% vs 16.3%, p=0.261). Moreover, cases had a median discharge delay of 3 days (p=0.008).
Current literature suggests a higher risk of pregnancy-related complications in patients with renal fibromuscular dysplasia (FMD). The aim of our study was to assess the nature and prevalence of ...pregnancy-related complications in patients subsequently diagnosed with FMD. A call for participation was sent to centers contributing to the European/International FMD Registry. Patients with at least 1 pregnancy were included. Data on pregnancy were collected through medical files and FMD characteristics through the European/International FMD Registry. Data from 534 pregnancies were obtained in 237 patients. Despite the fact that, in 96% of cases, FMD was not diagnosed before pregnancy, 40% of women (n=93) experienced pregnancy-related complications, mostly gestational hypertension (25%) and preterm birth (20%), while preeclampsia was reported in only 7.5%. Only 1 patient experienced arterial dissection and another patient an aneurysm rupture. When compared with patients without pregnancy-related complications, patients with complicated pregnancies were younger at FMD diagnosis (43 versus 51 years old;
<0.001) and had a lower prevalence of cerebrovascular FMD (30% versus 52%;
=0.003) but underwent more often renal revascularization (63% versus 40%,
<0.001). In conclusion, the prevalence of pregnancy-related complications such as gestational hypertension and preterm birth was high in patients with FMD, probably related to the severity of renal FMD. However, the prevalence of preeclampsia and arterial complications was low/moderate. These findings emphasize the need to screen hypertensive women for FMD to ensure revascularization before pregnancy if indicated and appropriate follow-up during pregnancy, without discouraging patients with FMD from considering pregnancy.
Purpose
Primary meningococcal arthritis (PMA) represents an uncommon clinical presentation of meningococcal infection, mainly reported among young people. Herein, a case of PMA of the knee in an ...elderly patient is described.
Case presentation
On January 2022, an 87-year-old patient arrived at hospital with continuous fever persisting for three days and a picture of pain, swelling, redness, and warmth of her left knee. An arthrocentesis was promptly performed and the inoculated synovial fluid turned positive with numerous Gram-negative diplococci at the microscopic examination. The identification of bacteria was done in 48 h using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF) MS systems (VITEK
®
MS—bioMérieux) and standard microbiological procedures (VITEK
®
2 NH ID card—bioMérieux). Both methods identified the strain as
N. meningitidis
. The meningococcal isolate belonged to the serogroup B (MenB), Sequence type (ST)-162/clonal complex (cc)162. Two grams of ceftriaxone twice a day were administered for 21 days; than cefditoren pivoxil 400 mg twice a day for further 6 weeks after discharge. In Italy, from 2018 to January 2022, among 135 MenB, 31 MenB/cc162 were identified, of which only the case here reported was associated with an atypical clinical presentation.
Review of the literature
A total of 41 cases of PMA caused by
N. meningitidis
was reported in the literature, but only four occurred in elderly. To our knowledgements, no cases of PMA caused by MenB were previously reported among patients of more than 65 years of age.
Background
Computed tomography (CT) and magnetic resonance (MR) represent the gold standard for evaluating intracranial tumours, such as meningiomas; most meningiomas can be managed by surveillance ...and clinical follow‐up, therefore, the ideal technology should be cheap, non‐invasive, safe and able to reduce radiation exposure. Transcranial colour‐coded duplex sonography (TCCS) can detect space‐occupying lesions, but its full potential for clinical practice is still unexpressed.
Aims and Methods
We describe the ability of TCCS to directly and accurately image, in a 77‐year‐old woman hospitalised for septic shock and coma, a suprasellar meningioma with a spatial resolution very similar to CT.
Results
The meningioma was clearly visualised as a roundish mass, with well‐defined borders, heterogeneously hyperechogenic compared with the surrounding brain structures; multiple intralesional calcifications were detectable as highly echogenic spots. Latero‐lateral and antero‐posterior diameters were well measurable.
Discussion
TCCS should not be considered as an alternative to CT and MR imaging, but it might have a complementary role, useful for use at the bedside in uncooperative or non‐transportable patients and for follow‐up, when an adequate acoustic window is guaranteed. Neurologists and neuroradiologists should further explore the full potential of this technology.
BackgroundComputed tomography (CT) and magnetic resonance (MR) represent the gold standard for evaluating intracranial tumours, such as meningiomas; most meningiomas can be managed by surveillance ...and clinical follow-up, therefore, the ideal technology should be cheap, non-invasive, safe and able to reduce radiation exposure. Transcranial colour-coded duplex sonography (TCCS) can detect space-occupying lesions, but its full potential for clinical practice is still unexpressed. Aims and MethodsWe describe the ability of TCCS to directly and accurately image, in a 77-year-old woman hospitalised for septic shock and coma, a suprasellar meningioma with a spatial resolution very similar to CT. ResultsThe meningioma was clearly visualised as a roundish mass, with well-defined borders, heterogeneously hyperechogenic compared with the surrounding brain structures; multiple intralesional calcifications were detectable as highly echogenic spots. Latero-lateral and antero-posterior diameters were well measurable. DiscussionTCCS should not be considered as an alternative to CT and MR imaging, but it might have a complementary role, useful for use at the bedside in uncooperative or non-transportable patients and for follow-up, when an adequate acoustic window is guaranteed. Neurologists and neuroradiologists should further explore the full potential of this technology.
To evaluate the cell response to DNA double-strand breaks induced by low and high linear energy transfer (LET) radiations when the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), an ...essential protein of the nonhomologous end-joining repair pathway, lacks kinase activity.
CHO10B2, a Chinese hamster ovary cell line, and its derived radiosensitive mutant cell line, irs-20, lacking DNA-PKcs activity, were evaluated after 0 to 3 Gy of γ-rays, plateau and Bragg peak protons, and lithium beams by clonogenic assay, and as a measurement of double-strand breaks, phosphorylated H2AX (γH2AX) foci number and size were quantified by immunocytofluorescence.
Irs-20 exhibited greater radiosensitivity and a higher amount of γH2AX foci than CHO10B2 at 6 hours after irradiation for all types of radiations. Remarkably, CHO10B2 and irs-20 maintained their difference in radiosensitivity after high-LET radiation. Six hours after low-LET radiations, irs-20 did not reach basal levels of γH2AX at high doses, whereas CHO10B2 recovered basal levels for all doses. After high-LET radiation, only CHO10B2 exhibited a reduction in γH2AX foci, but it never reached basal levels. Persistent foci in irs-20 confirmed a repair deficiency. Interestingly, after 30 minutes of high-LET radiation both cell lines exhibited large foci (size>0.9 μm2) related to the damage nature, whereas at 6 hours irs-20 showed a higher amount of large foci than CHO10B2, with a 7-fold increase at 3 Gy, that could also be associated to radiosensitivity.
We demonstrated, for the first time, an association between deficient DNA-PKcs activity and not only high levels of H2AX phosphorylation but also persistence and size increase of γH2AX foci after high-LET irradiation.
The Cyclin-dependent kinase inhibitor 1B (p27Kip1) is a key protein in the decision between proliferation and cell cycle exit. Quiescent cells show nuclear p27Kip1, but this protein is exported to ...the cytoplasm in response to proliferating signals. We recently reported that catalase treatment increases the levels of p27Kip1 in vitro and in vivo in a murine model. In order to characterize and broaden these findings, we evaluated the regulation of p27Kip1 by hydrogen peroxide (H(2)O(2)) in human melanoma cells and melanocytes. We observed a high percentage of p27Kip1 positive nuclei in melanoma cells overexpressing or treated with exogenous catalase, while non-treated controls showed a cytoplasmic localization of p27Kip1. Then we studied the levels of p27Kip1 phosphorylated (p27p) at serine 10 (S10) and at threonine 198 (T198) because phosphorylation at these sites enables nuclear exportation of this protein, leading to accumulation and stabilization of p27pT198 in the cytoplasm. We demonstrated by western blot a decrease in p27pS10 and p27pT198 levels in response to H(2)O(2) removal in melanoma cells, associated with nuclear p27Kip1. Melanocytes also exhibited nuclear p27Kip1 and lower levels of p27pS10 and p27pT198 than melanoma cells, which showed cytoplasmic p27Kip1. We also showed that the addition of H(2)O(2) (0.1 µM) to melanoma cells arrested in G1 by serum starvation induces proliferation and increases the levels of p27pS10 and p27pT198 leading to cytoplasmic localization of p27Kip1. Nuclear localization and post-translational modifications of p27Kip1 were also demonstrated by catalase treatment of colorectal carcinoma and neuroblastoma cells, extending our findings to these other human cancer types. In conclusion, we showed in the present work that H(2)O(2) scavenging prevents nuclear exportation of p27Kip1, allowing cell cycle arrest, suggesting that cancer cells take advantage of their intrinsic pro-oxidant state to favor cytoplasmic localization of p27Kip1.
Reactive oxygen species (ROS) are implicated in tumor transformation. The antioxidant system (AOS) protects cells from ROS damage. However, it is also hijacked by cancers cells to proliferate within ...the tumor. Thus, identifying proteins altered by redox imbalance in cancer cells is an attractive prognostic and therapeutic tool. Gene expression microarrays in A375 melanoma cells with different ROS levels after overexpressing catalase were performed. Dissimilar phenotypes by differential compensation to hydrogen peroxide scavenging were generated. The melanotic A375-A7 (A7) upregulated TYRP1, CNTN1 and UCHL1 promoting melanogenesis. The metastatic A375-G10 (G10) downregulated MTSS1 and TIAM1, proteins absent in metastasis. Moreover, differential coexpression of AOS genes (EPHX2, GSTM3, MGST1, MSRA, TXNRD3, MGST3 and GSR) was found in A7 and G10. Their increase in A7 improved its AOS ability and therefore, oxidative stress response, resembling less aggressive tumor cells. Meanwhile, their decrease in G10 revealed a disruption in the AOS and therefore, enhanced its metastatic capacity.These gene signatures, not only bring new insights into the physiopathology of melanoma, but also could be relevant in clinical prognostic to classify between non aggressive and metastatic melanomas.
3
-O
-Methylquercetin (3
O
MQ), a natural 3-
O-
methylflavonoid, was isolated from
Achyrocline satureioides
and purified using the high-performance counter current chromatography (HPCCC) on a ...semi-preparative scale. High-purity 3
O
MQ (98%) was obtained with excellent recovery (81.8% (w/w)) and good yield (190 mg/100 g of plant). Isolated 3
O
MQ was evaluated against the A375 human amelanotic melanoma cancer cell line and A375-derived with different degrees of aggressiveness (A375-A7, A375-G10, and A375-PCDNA3). The results showed that 3
O
MQ reduced the cell viability of all strains, demonstrating time- and dose-dependent responses. 3
O
MQ was used to obtain hydrogels for the topical treatment of melanoma. Thus, 3
O
MQ was incorporated into hypromellose hydrogels with/without different cyclodextrins (CDs). The 3
O
MQ formulations showed permeation/retention in all skin layers, namely stratum corneum, epidermis, and dermis. A significant amount of 3
O
MQ was found in the replication site of the melanoma cells (epidermis and dermis). Altogether, these results demonstrate that 3
O
MQ can be isolated from
Achyrocline satureioides
by HPCCC on a semi-preparative scale and exhibit cytotoxic activity against melanoma cells. Its incorporation into an HPMC hydrogel containing HP-β-CD yielded a formulation with excellent technological and biopharmaceutical characteristics for evaluating the topical management of melanoma.
Graphical abstract
Melanoma is an aggressive cancer with highly metastatic ability. We propose cofilin-1, a key protein in the regulation of actin dynamics and migration, as a prognostic marker. We determined cofilin-1 ...levels in a retrospective cohort of patients with melanomas and benign lesions of melanocytes (nevi) by immunohistochemistry. Higher cofilin-1 levels were found in malignant melanoma (MM) with Breslow Index (BI)>2 vs MM with BI<2, melanoma
(MIS) and nevi and also in MM with metastasis vs MM without detected metastasis. Kaplan-Meier survival curves were performed, clustering patients according to either the type of melanocytic lesions or cofilin-1 level. Survival curves demonstrated worse prognosis of patients with high vs low cofilin-1 levels. TCGA database analysis of melanoma also showed low survival in patients with upregulated cofilin-1 mRNA vs patients without alteration in CFL1 mRNA expression. As cofilin-1 has a dual function depending on its intracellular localization, we evaluated nuclear and cytoplasmic levels of cofilin-1 in melanoma and nevi samples by immunofluorescence. MM with high Breslow index and metastatic cells not only presented cytoplasmic cofilin-1, but also showed this protein at the nucleus. An increase in nuclear/cytoplasmic cofilin-1 mean fluorescence ratio was observed in MM with BI>2 vs MM with BI<2, MIS and nevi. In conclusion, an association of cofilin-1 levels with malignant features and an inverse correlation with survival were demonstrated. Moreover, this study suggests that not only the higher levels of cofilin-1, but also its nuclear localization can be proposed as marker of worse outcome of patients with melanoma.
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