Anthracycline-related cardiotoxicity in patients with breast cancer harboring mutational signature of homologous recombination deficiency (HRD).

BACKGROUND: The BRCA proteins play a key role in the homologous recombination (HR) pathway. Beyond BRCA1/2, other genes are involved in the HR repair (HRR). Due to the prominent role in the cellular repair process, pathogenic or likely pathogenic variants (PV/LPVs) in HRR genes may cause inadequate DNA damage repair in cardiomyocytes. PATIENTS AND METHODS: This was a multicenter, hospital-based, retrospective cohort study to investigate the heart toxicity from anthracycline-containing regimens (ACRs) in the adjuvant setting of breast cancer (BC) patients carrying germline BRCA PV/LPVs and no-BRCA HRR pathway genes. The left ventricular ejection fraction (LVEF) was assessed using cardiac ultrasound before starting ACR therapy and at subsequent time points according to clinical indications. RESULTS: Five hundred and three BC patients were included in the study. We predefined three groups: (i) BRCA cohort; (ii) no-BRCA cohort; (iii) variant of uncertain significance (VUS)/wild-type (WT) cohort. When baseline (T0) and post-ACR (T1) LVEFs between the three cohorts were compared, pre-treatment LVEF values were not different (BRCA1/2 versus HRR-no-BRCA versus VUS/WT cohort). Notably, during monitoring (T1, median 3.4 months), patients carrying BRCA or HRR no-BRCA germline pathogenic or likely pathogenic variants showed a statistically significant reduction of LVEF compared to baseline (T0). To assess the relevance of HRR on the results, we included the analysis of the subgroup of 20 BC patients carrying PV/LPVs in other genes not involved in HRR, such as mismatch repair genes (MUTYH, PMS2, MSH6). Unlike HRR genes, no significant differences in T0-T1 were found in this subgroup of patients. CONCLUSION: Our data suggest that deleterious variants in HRR genes, leading to impaired HR, could increase the sensitivity of cardiomyocytes to ACR in early BC patients. In this subgroup of patients, other measurements, such as the global longitudinal strain, and a more in-depth assessment of risk factors may be proposed in the future to optimize cardiovascular risk management and improve long-term survival.

Corrigendum to "Going for a stroll on lurasidone: Considerations on an atypical case of acute compartment syndrome of both legs" [Heliyon 9(4) (April 2023) e15047].

[This corrects the article DOI: 10.1016/j.heliyon.2023.e15047.].

Going for a stroll on lurasidone: Considerations on an atypical case of acute compartment syndrome of both legs.

Non-traumatic acute bilateral compartment syndrome is a rare condition that may lead to limb ischemia. We describe a case of this syndrome occurring after a five-kilometer walk in a young woman receiving chronic treatment with lurasidone, leading to a bilateral foot-drop and rhabdomyolysis of the anterolateral compartment of both legs. Due to her late presentation in the emergency department, we opted for a conservative approach, closely monitoring her renal function. We noticed a subsequent clinical and biochemical improvement over the following days, with the patient returning to her daily routine in a matter of weeks, despite a persisting bilateral foot drop. Since atypical antipsychotics are known to be associated with rhabdomyolysis, while possibly exerting a toxic effect on mitochondria, we hypothesize that a mild aerobic physical exertion might have triggered the event, in the context of an iatrogenic muscle susceptibility to oxidative distress.

Dermoscopic spectrum of mycosis fungoides: a retrospective observational study by the International Dermoscopy Society.

BACKGROUND: The dermoscopic features of classic patch stage mycosis fungoides (MF) have been described, but data on plaque and tumoral stage as well as rarer MF subtypes is limited. OBJECTIVE: To evaluate dermoscopic morphology and dermoscopic-pathological correlations of classic MF stages and investigate dermoscopic features of MF variants. METHODS: Patients with histopathologically confirmed lesions of classic MF (patch, plaque and tumoral stage) or folliculotropic, erythrodermic and poikilodermatous MF were included. Standardized evaluation of dermoscopic pictures of the included MF variants and comparative analysis and dermoscopic-pathological correlation assessment of different stages of classic MF were performed. RESULTS: A total of 118 instances were included (75 classic MF, 26 folliculotropic MF, 9 erythrodermic MF and 8 poikilodermatous MF). Linear/linear-curved vessels and white scales in the skin furrows were significantly associated with patch-stage MF, while clustered dotted vessels were related to plaque-stage MF and peripheral linear vessels with branches, ulceration and red globules separated by white lines to tumour-stage MF. Moreover, patchy white scales were significantly more common in patches and plaques compared to tumours, whereas focal bright white structureless areas were related to plaque and tumoral stage. Vessels histopathologically corresponded to dilated vascular structures in the dermis, orange structureless areas to either dermal hemosiderin (patch/plaque stage) or dense cellular infiltration (tumours), bright white lines/structureless areas to dermal fibrosis and ulceration to loss of epidermis. The main dermoscopic findings of folliculotropic MF were lack of hairs, dilated follicles and follicular plugs, while erythrodermic MF was mainly characterized by linear/dotted vessels, patchy white scales and focal orange structureless areas and poikilodermatous MF by focal white and brown structureless areas, white patchy scales and brown reticular lines. CONCLUSION: Dermoscopy may allow a more precise characterization of classic MF and reveal clues suggestive of the main MF variants.

Effects of respiratory muscle training on parasympathetic activity in diabetes mellitus.

This study verified the effects of respiratory muscle training (RMT) on hemodynamics, heart rate (HR) variability, and muscle morphology in rats with streptozotocin-induced diabetes mellitus (DM). Thirty-six male Wistar rats were randomized into 4 groups and 34 completed the study: i) sham-sedentary (Sham-ST; n=9); ii) sham-RMT (Sham-RMT; n=9); iii) DM-sedentary (DM-ST; n=8); and iv) DM-RMT (DM-RMT; n=8). Hemodynamics were assessed by central cannulation, and R-R intervals were measured by electrocardiogram. In addition, the effects of RMT on the cross-sectional area of the diaphragm, anterior tibial, and soleus muscles were analyzed. The induction of DM by streptozotocin resulted in weight loss, hyperglycemia, reduced blood pressure, and attenuated left ventricular contraction and relaxation (P<0.05). We also observed a decrease in root mean square of successive differences between adjacent RR intervals (RMSSD) index and in the cross-sectional area of the muscles assessed, specifically the diaphragm, soleus, and anterior tibial muscles in diabetic rats (P<0.05). Interestingly, RMT led to an increase in RMSSD in rats with DM (P<0.05). The induction of DM produced profound deleterious changes in the diaphragmatic and peripheral muscles, as well as impairments in cardiovascular hemodynamics and autonomic control. Nevertheless, RMT may beneficially attenuate autonomic changes and improve parasympathetic modulation.

Effects of respiratory muscle training on parasympathetic activity in diabetes mellitus

This study verified the effects of respiratory muscle training (RMT) on hemodynamics, heart rate (HR) variability, and muscle morphology in rats with streptozotocin-induced diabetes mellitus (DM). Thirty-six male Wistar rats were randomized into 4 groups and 34 completed the study: i) sham-sedentary (Sham-ST; n=9); ii) sham-RMT (Sham-RMT; n=9); iii) DM-sedentary (DM-ST; n=8); and iv) DM-RMT (DM-RMT; n=8). Hemodynamics were assessed by central cannulation, and R-R intervals were measured by electrocardiogram. In addition, the effects of RMT on the cross-sectional area of the diaphragm, anterior tibial, and soleus muscles were analyzed. The induction of DM by streptozotocin resulted in weight loss, hyperglycemia, reduced blood pressure, and attenuated left ventricular contraction and relaxation (P<0.05). We also observed a decrease in root mean square of successive differences between adjacent RR intervals (RMSSD) index and in the cross-sectional area of the muscles assessed, specifically the diaphragm, soleus, and anterior tibial muscles in diabetic rats (P<0.05). Interestingly, RMT led to an increase in RMSSD in rats with DM (P<0.05). The induction of DM produced profound deleterious changes in the diaphragmatic and peripheral muscles, as well as impairments in cardiovascular hemodynamics and autonomic control. Nevertheless, RMT may beneficially attenuate autonomic changes and improve parasympathetic modulation.

Altered shear stress on endothelial cells leads to remodeling of extracellular matrix and induction of angiogenesis.

Endothelial cells (ECs) are subjected to physical forces such as shear stress (SS) induced by blood flow that leads to significant changes in morphology, physiology and gene expression. The abnormal mechanical forces applied in the cardiovascular system can influence the development of conditions and diseases such as thrombosis, hypertension and atherosclerosis. This study investigated the expression of glycosaminoglycans (GAGs), proteoglycans and extracellular matrix molecules in ECs exposed to normal and altered SS. ECs were exposed to SS of 12 dyn/cm2 (artery physiological condition) and 4 dyn/cm2 (artery pathological condition). Subsequently, ECs were subjected to immunofluorescence, qPCR, GAG biosynthesis analyses and cell-based assays. SS induced changes in ECs morphology. There were other pathological consequences of altered SS, including inhibited adhesion, stimulation of migration and capillary-like tube formation, as well as increases of GAG synthesis. We observed higher expression of syndecan-4, perlecan, decorin, fibronectin and collagen III α1 and growth factors, including VEGF-A and TGFß-1. ECs exposed to SS displayed extracellular matrix remodeling as well as expression of cell-matrix and cell-cell interaction molecules. This study contributes to the understanding of how vascular biology is affected by mechanical forces and how these molecules can be affected in cardiovascular diseases.

Non-invasive CPAP in mild and moderate ARDS secondary to SARS-CoV-2.

BACKGROUND: During the COVID-19 outbreak, a very high number of infected patients developed pneumonia and many of them complicated with acute respiratory distress syndrome. The optimal management of respiratory failure and the role of lung ultrasound imaging in the evaluation of efficacy of treatment are unknown. METHODS: In March 2020 we treated 18 patients with mild and moderate ARDS secondary to SARS-CoV-2 with non-invasive continuous positive airway pressure therapy (NI-CPAP). All patients underwent lung ultrasound imaging to verify the entity of lung recruitment after NI-CPAP initiation. RESULTS: After one hour of treatment we observed a significant improvement in PaO2/FiO2 ratio in 10 patients. Notably, only 50 % of them reached an effective improvement in lung aeration detectable with lung ultrasound. In the other 50 % or patients the improvement in PaO2/FiO2 might be related to blood redistribution and reverse of hypoxic vasoconstriction. CONCLUSION: NI- CPAP is a valid therapeutic option in mild and moderate ARDS secondary SARS-CoV-2. Lung recruitment detected by means of lung ultrasound is a relevant but not the exclusive mechanism that underlies the therapeutic efficacy of NI-CPAP in this clinical setting.

Reaching task performance is associated to neuromuscular junction adaptations in rats with induced diabetes mellitus.

Upper limb performance is affected by diabetes mellitus (DM). Neuromuscular junction (NMJ) is a key structure to understand the relationship between performance and morphology in DM. The aim of the study was to analyze NMJ plasticity due to DM in an animal model and its relationship with the function of forelimbs in rats. Twelve Wistar rats were divided into control (C) and DM groups. Animals were trained to perform a grasping task, following procedures of habituation, shaping, and reaching task. DM was induced using streptozotocin. Forelimb neuromuscular performance for dexterity was evaluated one day before DM induction and five weeks following induction. After that, biceps, triceps, and finger flexors and extensors were removed. Connective tissue and muscle fiber cross-sectional area (CSA) were measured. NMJ was assessed by its morphometric characteristics (area, perimeter, and maximum diameter), using ImageJ software. Motor performance analyses were made using single pellet retrieval task performance test. Student's t-test was used for comparisons between groups. A significant decrease in all NMJ morphometric parameters was observed in the DM group compared with the C group. Results showed that DM generated NMJ retraction in muscles involved in a reaching task. These alterations are related to signs of muscular atrophy and to poor reaching task performance. In conclusion, induced DM caused NMJ retraction and muscular atrophy in muscles involved in reaching task performance. Induced DM caused significantly lower motor performance, especially in the final moments of evaluation, when DM compromised the tropism of the muscular tissue.

Standardization of dermoscopic terminology and basic dermoscopic parameters to evaluate in general dermatology (non-neoplastic dermatoses): an expert consensus on behalf of the International Dermoscopy Society.

BACKGROUND: Over the last few years, several articles on dermoscopy of non-neoplastic dermatoses have been published, yet there is poor consistency in the terminology among different studies. OBJECTIVES: We aimed to standardize the dermoscopic terminology and identify basic parameters to evaluate in non-neoplastic dermatoses through an expert consensus. METHODS: The modified Delphi method was followed, with two phases: (i) identification of a list of possible items based on a systematic literature review and (ii) selection of parameters by a panel of experts through a three-step iterative procedure (blinded e-mail interaction in rounds 1 and 3 and a face-to-face meeting in round 2). Initial panellists were recruited via e-mail from all over the world based on their expertise on dermoscopy of non-neoplastic dermatoses. RESULTS: Twenty-four international experts took part in all rounds of the consensus and 13 further international participants were also involved in round 2. Five standardized basic parameters were identified: (i) vessels (including morphology and distribution); (ii) scales (including colour and distribution); (iii) follicular findings; (iv) 'other structures' (including colour and morphology); and (v) 'specific clues'. For each of them, possible variables were selected, with a total of 31 different subitems reaching agreement at the end of the consensus (all of the 29 proposed initially plus two more added in the course of the consensus procedure). CONCLUSIONS: This expert consensus provides a set of standardized basic dermoscopic parameters to follow when evaluating inflammatory, infiltrative and infectious dermatoses. This tool, if adopted by clinicians and researchers in this field, is likely to enhance the reproducibility and comparability of existing and future research findings and uniformly expand the universal knowledge on dermoscopy in general dermatology. What's already known about this topic? Over the last few years, several papers have been published attempting to describe the dermoscopic features of non-neoplastic dermatoses, yet there is poor consistency in the terminology among different studies. What does this study add? The present expert consensus provides a set of standardized basic dermoscopic parameters to follow when evaluating inflammatory, infiltrative and infectious dermatoses. This consensus should enhance the reproducibility and comparability of existing and future research findings and uniformly expand the universal knowledge on dermoscopy in general dermatology.

Combination of photodynamic therapy with 5-aminolaevulinic acid and microneedling in the treatment of alopecia areata resistant to conventional therapies: our experience with 41 patients.

Alopecia areata (AA) is a complex immune-mediated disorder, which is difficult to treat. The available treatment options seem to have limited benefit, help only some patients and have a high relapse rate. We evaluated a new therapeutic option for moderate to severe AA based on the combination of photodynamic therapy (PDT) with 5-aminolaevulinic acid (ALA) and microneedling (MN). In total, 14 patients were enrolled, and these were randomly divided into 3 groups: Group A (MN alone; n = 9), Group B (ALA-PDT alone; n = 15) and Group C (combination of MN and ALA-PDT; n = 17). All patients were treated once every 3 weeks for a total of six treatments. The best clinical outcome was achieved in Group C, with complete hair regrowth observed in three patients, and an improvement of ≥ 50% and < 50% of the treated areas obtained in seven and six patients, respectively. Our report suggests that combination of ALA-PDT with MN could be an additional therapeutic option in moderate to severe AA, as MN allows better skin penetration of ALA and subsequent indirect immunosuppression.