Pregnenolone-methyl-ether enhances CLIP170 and microtubule functions improving spine maturation and hippocampal deficits related to CDKL5 deficiency.

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) cause CDKL5 deficiency disorder (CDD), a neurodevelopmental disease characterized by severe infantile seizures and intellectual disability. The absence of CDKL5 in mice causes defective spine maturation that can at least partially explain the cognitive impairment in CDKL5 patients and CDD mouse models. The molecular basis for such defect may depend on the capacity of CDKL5 to regulate microtubule (MT) dynamics through its association with the MT-plus end tracking protein CLIP170 (cytoplasmic linker protein 170). Indeed, we here demonstrate that the absence of CDKL5 causes CLIP170 to be mainly in a closed inactive conformation that impedes its binding to MTs. Previously, the synthetic pregnenolone analogue, pregnenolone-methyl-ether (PME), was found to have a positive effect on CDKL5-related cellular and neuronal defects in vitro. Here, we show that PME induces the open active conformation of CLIP170 and promotes the entry of MTs into dendritic spines in vitro. Furthermore, the administration of PME to symptomatic Cdkl5-knock-out mice improved hippocampal-dependent behavior and restored spine maturation and the localization of MT-related proteins in the synaptic compartment. The positive effect on cognitive deficits persisted for 1 week after treatment withdrawal. Altogether, our results suggest that CDKL5 regulates spine maturation and cognitive processes through its control of CLIP170 and MT dynamics, which may represent a novel target for the development of disease-modifying therapies.

Changes in blood serum parameters in farmed rainbow trout (Oncorhynchus mykiss) during a piscine lactococcosis outbreak.

The aquaculture sector plays a vital role in global food security, yet it grapples with significant challenges posed by infectious diseases. Piscine lactococcosis is one of the significant threats in rainbow trout aquaculture due to its potential to cause severe economic losses through mortalities, reduced growth rates, and increased susceptibility to other pathogens. It poses challenges in disease management strategies, impacting the sustainability and profitability of rainbow trout farming. The current study focuses on the variations in serum blood parameters of farmed rainbow trout Oncorhynchus mykiss during a lactococcosis outbreak caused by Lactococcus garvieae. Blood samples were collected for biochemical analysis, fish were examined for parasites and bacteria, and DNA from bacterial colonies was PCR-amplified and sequenced for identification. Overall, 13 biochemical parameters, including proteins, enzymes, lipids, chemicals, and minerals, were measured in serum blood samples from both diseased and healthy fish. The results indicate significant alterations in the levels of these parameters during the outbreak, highlighting the impact of infections on the blood profile of farmed rainbow trout. Urea levels were significantly higher in diseased fish compared to controls, and creatinine, phosphorus, and magnesium also showed similar trends. Alanine aminotransferase and total protein levels were higher in control fish. Chloride levels differed significantly between groups. Iron levels were higher in controls and lower in diseased fish. No significant differences were found in other parameters. This study reveals significant changes in serum blood parameters of rainbow trout during a lactococcosis outbreak caused by L. garvieae. These changes highlight the potential of these parameters as tools for monitoring health status, stress, and aquaculture management. Continuous monitoring can provide valuable insights into disease severity and overall fish health, aiding in the development of improved management practices. The presented data contribute to understanding the pathophysiology of piscine lactococcosis and developing effective mitigation strategies for farmed rainbow trout.

Development of collagenous scaffolds for wound healing: characterization and in vivo analysis.

The development of wound dressings from biomaterials has been the subject of research due to their unique structural and functional characteristics. Proteins from animal origin, such as collagen and chitosan, act as promising materials for applications in injuries and chronic wounds, functioning as a repairing agent. This study aims to evaluate in vitro effects of scaffolds with different formulations containing bioactive compounds such as collagen, chitosan, N-acetylcysteine (NAC) and ε-poly-lysine (ε-PL). We manufactured a scaffold made of a collagen hydrogel bioconjugated with chitosan by crosslinking and addition of NAC and ε-PL. Cell viability was verified by resazurin and live/dead assays and the ultrastructure of biomaterials was evaluated by SEM. Antimicrobial sensitivity was assessed by antibiogram. The healing potential of the biomaterial was evaluated in vivo, in a model of healing of excisional wounds in mice. On the 7th day after the injury, the wounds and surrounding skin were processed for evaluation of biochemical and histological parameters associated with the inflammatory process. The results showed great cell viability and increase in porosity after crosslinking while antimicrobial action was observed in scaffolds containing NAC and ε-PL. Chitosan scaffolds bioconjugated with NAC/ε-PL showed improvement in tissue healing, with reduced lesion size and reduced inflammation. It is concluded that scaffolds crosslinked with chitosan-NAC-ε-PL have the desirable characteristics for tissue repair at low cost and could be considered promising biomaterials in the practice of regenerative medicine.

Management of acute coronary syndromes in older adults.

Older patients are underrepresented in prospective studies and randomized clinical trials of acute coronary syndromes (ACS). Over the last decade, a few specific trials have been conducted in this population, allowing more evidence-based management. Older adults are a heterogeneous, complex, and high-risk group whose management requires a multidimensional clinical approach beyond coronary anatomic variables. This review focuses on available data informing evidence-based interventional and pharmacological approaches for older adults with ACS, including guideline-directed management. Overall, an invasive approach appears to demonstrate a better benefit-risk ratio compared to a conservative one across the ACS spectrum, even considering patients' clinical complexity and multiple comorbidities. Conversely, more powerful strategies of antithrombotic therapy for secondary prevention have been associated with increased bleeding events and no benefit in terms of mortality reduction. An interdisciplinary evaluation with geriatric assessment should always be considered to achieve a holistic approach and optimize any treatment on the basis of the underlying biological vulnerability.

Percutaneous left atrial appendage occlusion in a frail, high-risk, octogenarian patient population, after having undergone transcatheter aortic valve implantation.

BACKGROUND: Percutaneous left atrial appendage occlusion (LAAO) represents an alternative stroke prevention method in patients with atrial fibrillation and an increased bleeding risk, chronic kidney disease or contraindications to oral anticoagulants. Aim of our study was to evaluate the feasibility and safety of percutaneous LAAO in high-risk, frail patients having undergone transcatheter aortic valve implantation (TAVI). METHODS: Thirty-one patients having undergone TAVI and scheduled for LAAO were prospectively included in our study. RESULTS: Implantation was successful in 29 of 31 cases (93.5%).There were no patients that developed a major acute cardiovascular event, stroke, or device dislocation/embolization. There was a single case of major bleeding (3.2%) and 3 cases of acute kidney injury (9.7%). At 3 months, no patients experienced a stroke, one patient had a device-related thrombus (3.4%), one patient showed a significant peri-device leak, and one patient had a persistent iatrogenic atrial septal defect. CONCLUSIONS: Our study shows that percutaneous LAAO may represent a feasible alternative strategy for stroke prevention, that can be safely performed in high-risk, multimorbid patients with high bleeding risk or contraindications to oral anticoagulation.

Loss of CDKL5 Causes Synaptic GABAergic Defects That Can Be Restored with the Neuroactive Steroid Pregnenolone-Methyl-Ether.

CDKL5 deficiency disorder (CDD) is an X-linked neurodevelopmental disorder characterised by early-onset drug-resistant epilepsy and impaired cognitive and motor skills. CDD is caused by mutations in cyclin-dependent kinase-like 5 (CDKL5), which plays a well-known role in regulating excitatory neurotransmission, while its effect on neuronal inhibition has been poorly investigated. We explored the potential role of CDKL5 in the inhibitory compartment in Cdkl5-KO male mice and primary hippocampal neurons and found that CDKL5 interacts with gephyrin and collybistin, two crucial organisers of the inhibitory postsynaptic sites. Through molecular and electrophysiological approaches, we demonstrated that CDKL5 loss causes a reduced number of gephyrin puncta and surface exposed γ2 subunit-containing GABAA receptors, impacting the frequency of miniature inhibitory postsynaptic currents, which we ascribe to a postsynaptic function of CDKL5. In line with previous data showing that CDKL5 loss impacts microtubule (MT) dynamics, we showed that treatment with pregnenolone-methyl-ether (PME), which promotes MT dynamics, rescues the above defects. The impact of CDKL5 deficiency on inhibitory neurotransmission might explain the presence of drug-resistant epilepsy and cognitive defects in CDD patients. Moreover, our results may pave the way for drug-based therapies that could bypass the need for CDKL5 and provide effective therapeutic strategies for CDD patients.

Dynamics of cerebral oxygenation during rapid ventricular pacing and its impact on outcome in transfemoral transcatheter aortic valve implantation.

BACKGROUND: Cerebral O2 saturation (ScO2 ) reflects cerebral perfusion and can be measured noninvasively by near-infrared spectroscopy (NIRS). OBJECTIVES: In this pilot study, we describe the dynamics of ScO2 during TAVI in nonventilated patients and its impact on procedural outcome. METHODS AND RESULTS: We measured ScO2 of both frontal lobes continuously by NIRS in 50 consecutive analgo-sedated patients undergoing transfemoral TAVI (female 58%, mean age 80.8 years). Compared to baseline ScO2 dropped significantly during RVP (59.3% vs. 53.9%, p < .01). Five minutes after RVP ScO2 values normalized (post RVP 62.6% vs. 53.9% during RVP, p < .01; pre 61.6% vs. post RVP 62.6%, p = .53). Patients with an intraprocedural pathological ScO2 decline of >20% (n = 13) had higher EuroSCORE II (3.42% vs. 5.7%, p = .020) and experienced more often delirium (24% vs. 62%, p = .015) and stroke (0% vs. 23%, p < .01) after TAVI. Multivariable logistic regression revealed higher age and large ScO2 drops as independent risk factors for delirium. CONCLUSIONS: During RVP ScO2 significantly declined compared to baseline. A ScO2 decline of >20% is associated with a higher incidence of delirium and stroke and a valid cut-off value to screen for these complications. NIRS measurement during TAVI procedure may be an easy to implement diagnostic tool to detect patients at high risks for cerebrovascular complications and delirium.

SARS-CoV-2 pneumonia succesfully treated with cpap and cycles of tripod position: a case report.

BACKGROUND: Pneumonia induced by 2019 Coronavirus (COVID-19) is characterized by hypoxemic respiratory failure that may present with a broad spectrum of clinical phenotypes. At the beginning, patients may have normal lung compliance and be responsive to noninvasive ventilatory support, such as CPAP. However, the transition to more severe respiratory failure - Severe Acute Respiratory Syndrome (SARS-CoV-2), necessitating invasive ventilation is often abrupt and characterized by a severe V/Q mismatch that require cycles of prone positioning. The aim of this case is to report the effect on gas exchange, respiratory mechanics and hemodynamics of tripod (or orthopneic sitting position) used as an alternative to prone position in a patient with mild SARS-CoV-2 pneumonia ventilated with helmet CPAP. CASE PRESENTATION: A 77-year-old awake and collaborating male patient with mild SARS-CoV-2 pneumonia and ventilated with Helmet CPAP, showed sudden worsening of gas exchange without dyspnea. After an unsuccessful attempt of prone positioning, we alternated three-hours cycles of semi-recumbent and tripod position, still keeping him in CPAP. Arterial blood gases (PaO2/FiO2, PaO2, SaO2, PaCO2 and A/a gradient), respiratory (VE, VT, RR) and hemodynamic parameters (HR, MAP) were collected in the supine and tripod position. Cycles of tripod position were continued for 3 days. The patient had a clinically important improvement in arterial blood gases and respiratory parameters, with stable hemodynamic and was successfully weaned and discharged to ward 10 days after pneumonia onset. CONCLUSIONS: Tripod position during Helmet CPAP can be applied safely in patients with mild SARS-CoV-2 pneumonia, with improvement of oxygenation and V/Q matching, thus reducing the need for intubation.

NLRP12 gene mutations and auto-inflammatory diseases: ever-changing evidence.

Systemic auto-inflammatory diseases (SAID) are a group of rare inherited conditions characterized by a dysregulation of the immune system and associated with recurrent episodes of fever and systemic inflammation. Patients with NLRP12 variants develop a rare autosomal dominant condition known as familial cold-induced autoinflammatory syndrome (FCAS2, OMIM #611762) that has been related to several different clinical manifestations including autoimmunity and immune deficiencies. In past years, several new variants have been described; however, their clinical relevance is sometimes uncertain, especially when they have been detected in healthy subjects. To our knowledge 61 patients with NLRP12 variants have been reported so far in the literature. Here we report the case of a 33-year-old woman with a history of recurrent fever and symmetric and additive poly-arthritis, fulfilling diagnostic criteria for RA, who was found to harbour two variants in the NLRP12 gene (OMIM *609648) and provide a review of the literature on similar cases.

Short-term decrease of left atrial size predicts clinical outcome in patients with severe aortic stenosis undergoing TAVR.

OBJECTIVES: We investigated whether transcatheter aortic valve replacement (TAVR) results in a short-term decrease in left atrium (LA) size and whether such decrease may predict patients' clinical outcome. BACKGROUND: Increased LA size is a hallmark of severe aortic stenosis (AS) and is associated with adverse patients' cardiovascular outcome. Whether TAVR may lead to a decrease in LA size is not known. METHODS AND RESULTS: Hundred and four patients with severe symptomatic AS and dilated LA undergoing TAVR were enrolled. LA volume was assessed by echocardiography before and shortly after TAVR (median time: 7 days). Composite rate of death and hospitalization for acutely decompensated heart failure (HF) was recorded and clinical status was assessed through NYHA-class evaluation at 12 months median follow-up. After TAVR, 49 patients (47%) demonstrated a decrease in LA volume. Despite a similar baseline NYHA class, patients with decrease in LA size had significant better improvement in clinical status respect to patients with unvaried LA size (NYHA post: 1.2 ± 0.6 vs. 1.8 ± 1.1, p = .001; NYHA reduction: -1.6 ± 0.9 vs. -0.9 ± 1.0, p = .002, respectively). Moreover, these patients had a significantly reduced rate of death or HF-hospitalization (4 vs. 29%, p = .001) and a significantly longer event-free-survival from Kaplan-Meier curves (p = .003). COX regression analysis showed that, among echocardiographic parameters, decrease in LA size was an independent predictor of clinical outcome (HR: 0.149, CI: 0.034-0.654, p = .012). CONCLUSIONS: The lack of decrease in LA size shortly after TAVR is associated with significantly higher rates of death and HF-hospitalization, as well as with impaired improvement in clinical status during long-term follow-up.

Life beyond 5 Years after TAVI: Patients' Perceived Health Status and Long-Term Outcome after Transcatheter Aortic Valve Implantation.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is currently recommended for patients with severe aortic stenosis at intermediate or high surgical risk. The decision process during TAVI evaluation includes a thorough benefit-risk assessment, and knowledge about long-term benefits and outcomes may improve patients' expectation management. OBJECTIVE: To evaluate patients' perceived health status and self-reported long-term outcome more than 5 years after TAVI. METHODS AND RESULTS: Demographic and procedure data were obtained from all patients treated with TAVI at our institution from 2006 to 2012. A cross-sectional survey was conducted on the patients alive, measuring health status, including the EQ-5D-5L questionnaire, and clinical outcomes. 103 patients (22.8%) were alive at a median follow-up period of 7 years (5.4-9.8). 99 (96%) of the 103 patients were included in the final analysis. The mean age at follow-up was 86.5 years ± 8.0 years, and 56.6% were female. Almost all patients (93.9%) described an improvement of their quality of life after receiving TAVI. At late follow-up, the mean utility index and EQ-VAS score were 0.80 ± 0.20 and 58.49 ± 11.49, respectively. Mobility was found to be the most frequently reported limitation (85.4%), while anxiety/depression was the least frequently reported limitation (19.8%). With respect to functional class, 64.7% were in New York Heart Association (NYHA) class III or IV, compared to 67.0% prior to TAVI (p=0.51). Self-reported long-term outcomes revealed mainly low long-term complication rates. 74 total hospitalizations were reported after TAVI, and among those 43% for cardiovascular reasons. Within cardiovascular rehospitalizations, new pacemaker implantations were the most frequently reported (18.9%), followed by cardiac decompensation and coronary heart disease (15.6%). CONCLUSION: The majority of the patients described an improvement of health status after TAVI. More than five years after TAVI, the patients' perceived health status was satisfactory, and the incidence of clinical events and hospitalizations was very low.

Microtubules: A Key to Understand and Correct Neuronal Defects in CDKL5 Deficiency Disorder?

CDKL5 deficiency disorder (CDD) is a severe neurodevelopmental encephalopathy caused by mutations in the X-linked CDKL5 gene that encodes a serine/threonine kinase. CDD is characterised by the early onset of seizures and impaired cognitive and motor skills. Loss of CDKL5 in vitro and in vivo affects neuronal morphology at early and late stages of maturation, suggesting a link between CDKL5 and the neuronal cytoskeleton. Recently, various microtubule (MT)-binding proteins have been identified as interactors of CDKL5, indicating that its roles converge on regulating MT functioning. MTs are dynamic structures that are important for neuronal morphology, migration and polarity. The delicate control of MT dynamics is fundamental for proper neuronal functions, as evidenced by the fact that aberrant MT dynamics are involved in various neurological disorders. In this review, we highlight the link between CDKL5 and MTs, discussing how CDKL5 deficiency may lead to deranged neuronal functions through aberrant MT dynamics. Finally, we discuss whether the regulation of MT dynamics through microtubule-targeting agents may represent a novel strategy for future pharmacological approaches in the CDD field.

Anti-polysaccharide and anti-diphtheria protective antibodies after 13-valent pneumococcal conjugate vaccination in rheumatoid arthritis patients under immunosuppressive therapy.

Immunogenicity of 13-valent pneumococcal polysaccharide (PnPS) conjugate vaccine (PCV13) was evaluated in 38 rheumatoid arthritis patients under immunosuppressive treatment and 20 healthy controls (HC). Antibodies to all PnPS and diphtheria-toxin analogue conjugate protein were measured pre- (T0), 1 (T1), 6 (T2), 12 (T3) months post-immunization. Patients and HC had similar response to individual PnPS. Mean antibody levels to all PnPS but one doubled at T1 compared with T0, with T3 persistence for only 8-7/13 PnPS. Baseline antibody levels was inversely associated with the rate of responders at T1 (T1/T0≥2) to 11/13 PnPS. Few subjects reached protective IgG levels against some serotypes frequently isolated in Italian patients with invasive pneumococcal disease. Antibody response was not influenced by therapy, except the one to PS7F, which was reduced by tumor necrosis factor-α-inhibitors. Vaccination increased also anti-diphtheria IgG. Despite this study substantially confirmed the PCV13 immunogenicity in immunocompromised patients, it also revealed some limitations.

Percutaneous pulmonary valve implantation for reconstruction of a patch-repaired right ventricular outflow tract.

Percutaneous pulmonary valve implantation (PPVI) is nowadays an accepted treatment option to repair post-surgical conduit dysfunction of the right ventricular outflow tract (RVOT). In addition, many patients need a pulmonary valve to reconstruct a hemodynamically incompetent native or conduit free outflow tract. Based on our experience with percutaneous stent-valve placement in a cohort of 125 patients, we report here transvenous reconstruction of a conduit-free, patch repaired outflow tract by utilizing balloon-expandable stent-valves in 23 patients with a median age of 22 years (5-60 years). In 20 patients, the step-by-step procedure was performed uneventful with the aimed success. Severe RVOT dysfunction in term of a clinical relevant regurgitation could be changed to mild, as it was confirmed by follow-up color Doppler echocardiography. In a 5-year-old girl a Melody® valve was placed as a surgical-interventional hybrid approach. In one patient, the procedure was complicated by stent embolization during preparation of the RVOT for stent-valve implantation. Reposition of the embolized stent was nevertheless successful for finishing percutaneous valve-implantation. In one patient, surgical approach became necessary because of the inability to advance the balloon-mounted stent-valve through a pre-stented RVOT. Considering the current available balloon-expandable stent-valves, transvenous pulmonary valve implantation is feasible to treat even an incompetent conduit-free RVOT. However, preparation of the RVOT by pre-stenting, in most patients with more than two stents in telescope technique remains challenging. Reconstruction of RVOT by the current available valves is promising only for a carefully selected group of patients.

Transcatheter Repair of Functional Mitral Regurgitation in Heart Failure Patients　- A Meta-Analysis of 23 Studies on MitraClip Implantation.

BACKGROUND: The aim of this study was to investigate long-term survival, clinical status, and echocardiographic findings of patients with severe functional mitral regurgitation (FMR) undergoing MitraClip (MC) treatment and to explore the role of baseline features on outcome. Methods and Results: Randomized and observational studies of FMR patients undergoing MC treatment were collected to evaluate the overall survival, New York Heart Association (NYHA) class and echocardiographic changes after MC treatment. Baseline parameters associated with mortality and echocardiographic changes were also investigated. Across 23 studies enrolling 3,253 patients, the inhospital death rate was 2.31%, whereas the mortality rate was 5.37% at 1 month, 11.87% at 6 months, 18.47% at 1 year and 31.08% at 2 years. Mitral regurgitation Grade <3+ was observed in 92.76% patients at discharge and in 83.36% patients at follow-up. At follow-up, 76.63% of patients NYHA Class I-II and there were significant improvements in left ventricular (LV) volume, ejection fraction, and pulmonary pressure. Atrial fibrillation (AF) had a significant negative effect on 1-year survival (ß=0.18±0.06; P=0.0047) and on the reduction in LV end-diastolic and end-systolic volumes (ß=-1.05±0.47 [P=0.0248] and ß=-2.60±0.53 [P=0.0024], respectively). CONCLUSIONS: MC results in durable reductions in mitral regurgitation associated with significant clinical and echocardiographic improvements in heart failure patients. AF negatively affects LV reverse remodeling and 1-year survival after MC treatment.

Analysis of Gut Microbiota in Rheumatoid Arthritis Patients: Disease-Related Dysbiosis and Modifications Induced by Etanercept.

A certain number of studies were carried out to address the question of how dysbiosis could affect the onset and development of rheumatoid arthritis (RA), but little is known about the reciprocal influence between microbiota composition and immunosuppressive drugs, and how this interaction may have an impact on the clinical outcome. The aim of this study was to characterize the intestinal microbiota in a groups of RA patients treatment-naïve, under methotrexate, and/or etanercept (ETN). Correlations between the gut microbiota composition and validated immunological and clinical parameters of disease activity were also evaluated. In the current study, a 16S analysis was employed to explore the gut microbiota of 42 patients affected by RA and 10 healthy controls. Disease activity score on 28 joints (DAS-28), erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, anti-cyclic citrullinated peptides, and dietary and smoking habits were assessed. The composition of the gut microbiota in RA patients free of therapy is characterized by several abnormalities compared to healthy controls. Gut dysbiosis in RA patients is associated with different serological and clinical parameters; in particular, the phylum of Euryarchaeota was directly correlated to DAS and emerged as an independent risk factor. Patients under treatment with ETN present a partial restoration of a beneficial microbiota. The results of our study confirm that gut dysbiosis is a hallmark of the disease, and shows, for the first time, that the anti-tumor necrosis factor alpha (TNF-α) ETN is able to modify microbial communities, at least partially restoring a beneficial microbiota.

Hedgehog signalling pathway orchestrates angiogenesis in triple-negative breast cancers.

BACKGROUND: Several evidences suggest a marked angiogenic dependency in triple-negative breast cancer (TNBC) tumorigenesis and a potential sensitivity to anti-angiogenic agents. Herein, the putative role of Hedgehog (Hh) pathway in regulating TNBC-dependent angiogenesis was investigated. METHODS: Expression and regulation of the Hh pathway transcription factor glioma-associated oncogene homolog1 protein (GLI1) were studied on the endothelial compartment and on TNBC-initiated angiogenesis. To evaluate the translational relevance of our findings, the combination of paclitaxel with the Smo inhibitor NVP-LDE225 was tested in TNBC xenografted mice. RESULTS: Tissue microarray analysis on 200 TNBC patients showed GLI1 overexpression paired with vascular endothelial growth factor receptor 2 (VEGFR2) expression. In vitro, Hh pathway promotes TNBC progression in an autocrine manner, regulating the VEGF/VEGFR2 loop on cancer cell surface, and in a paracrine manner, orchestrating tumour vascularisation. These effects were counteracted by Smo pharmacological inhibition. In TNBC xenografted mice, scheduling NVP-LDE225 rather than bevacizumab provided a better sustained inhibition of TNBC cells proliferation and endothelial cells organisation. CONCLUSIONS: This study identifies the Hh pathway as one of the main regulators of tumour angiogenesis in TNBC, thus suggesting Hh inhibition as a potential new anti-angiogenic therapeutic option to be clinically investigated in GLI1 overexpressing TNBC patients.

TCD4pos lymphocytosis in rheumatoid and psoriatic arthritis patients following TNFα blocking agents.

BACKGROUND: Lymphocyte expansion and true lymphocytosis are commonly observed in the everyday clinical practice. The meaning of such phenomenon is often poorly understood so that discrimination between benign and malignant lymphocytosis remains difficult to establish. This is mainly true when lymphocytosis rises in patients affected by immune-mediated chronic inflammatory diseases under immunosuppressive treatment, conditions potentially associated with lymphomagenesis. In this brief report the development of mild T CD4pos lymphocytosis in a group of patients with chronic arthritis under anti-TNF-α treatment is described. METHODS: Two hundred eight rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients have been evaluated longitudinally for at least 1-year before and 2-years after anti-TNF-α therapy introduction for the possible appearance of a lymphocyte expansion. In patients who developed lymphocyte expansion, T, B and NK cells were analysed. RESULTS: Twenty-five out of 208 (12%) subjects developed a mild T CD4pos lymphocytosis, during anti-TNF-α therapy, which reverted after its interruption. Higher lymphocyte count, more frequent use of steroids and shorter disease duration, before biological therapy start, have emerged as risk factors for lymphocytosis development. CONCLUSIONS: This is the first longitudinal cohort study evaluating the onset of lymphocytosis in RA and PsA patients under anti-TNF-α treatment and its possible clinical relevance. A mild T CD4pos lymphocytosis has been observed in 12% of RA and PsA patients probably related to anti-TNF-α treatment as previously reported by anecdotal cases. Patients with higher baseline lymphocyte count, use of steroids and shorter disease duration before the introduction of biologic therapy, seem to be prone to develop this laboratory reversible abnormality.

Coronary Atherosclerotic Plaque Characteristics and Cardiovascular Risk Factors　- Insights From an Optical Coherence Tomography Study.

BACKGROUND: The association between cardiovascular risk factors (CVRF) and the risk of coronary events is widely acknowledged. Whether individual risk factors may be associated with distinct plaque characteristics is currently unclear. We investigated the relationship between CVRF and coronary plaque burden and phenotype.Methods and Results:We assessed coronary atherosclerotic plaque characteristics by optical coherence tomography in 67 patients with stable coronary artery disease undergoing coronary angiography. The plaque burden and the distinct plaque phenotypes were compared with regard to different CVRF. Overall plaque burden was significantly greater in patients with diabetes mellitus (P=0.010), prediabetes (P=0.035) and obesity (P=0.024), and correlated with the number of CVRF (R=0.358, P=0.003). Patients with diabetes had a greater extent of fibroatheroma (P=0.015), calcific fibroatheroma (P=0.031), thin-cap fibroatheroma (TCFA-P=0.011) and plaque erosion (P=0.002). Obese patients showed a greater extent of fibroatheroma (P=0.007), TCFA (P=0.015) and macrophage load (P=0.043). The number of CVRF correlated with fibroatheroma (R=0.425, P<0.001), calcific fibroatheroma (R=0.321, P=0.008), TCFA (R=0.347, P=0.004), macrophage load (R=0.314, P=0.010) and erosion (R=0.271, P=0.029). In the multivariate analysis, altered glycemic status and obesity were the only independent predictors of TCFA (P=0.026 and P=0.046, respectively), whereas altered glycemic status was the only independent predictor of plaque erosion (P=0.001). CONCLUSIONS: Patients with diabetes, prediabetes and obesity show more extensive coronary atherosclerosis and more vulnerable plaque phenotypes.

Percutaneous Therapy of a Stenotic Parachute Mitral Valve Previously Treated by Surgery.

Parachute mitral valve (PMV) is a congenital heart anomaly which consists of a unifocal attachment of the mitral valve chordae into a single or dominant papillary muscle. This morphological anomaly determines the impairment of mitral leaflet motion, resulting in different grades of mitral stenosis. Due to its frequent association with other congenital cardiac defects requiring surgical correction, the therapy of a relevant stenotic PMV is usually represented by surgical commissurotomy. Herein is reported the case of a PMV treated by surgery in infancy, which showed a severe restenosis after 34 years and was successfully treated by percutaneous valvuloplasty with the additional creation of a restrictive atrial communication.