Impact of the COVID-19 pandemic on the Italian national viral hepatitis surveillance: an interrupted time series analysis, 2006-2022.

OBJECTIVES: This study aimed to assess the impact of the COVID-19 pandemic on national surveillance of viral hepatitis in Italy. STUDY DESIGN: Interrupted time series analysis. METHODS: Using an interrupted time series analysis with a customised AutoRegressive Integrated Moving Average model on hepatitis cases reported to the Integrated Epidemiological System of Acute Viral Hepatitis from 2006 to 2022, we examined trends in incidence, time to diagnosis and time to epidemiological investigations for hepatitis A, hepatitis B and hepatitis C. RESULTS: The quarterly incidence of hepatitis B (-0.251, P = 0.05) and hepatitis C (-0.243, P = 0.003) significantly decreased with the onset of the pandemic. Surveillance times for hepatitis B (5.496, P < 0.001) and hepatitis C (35.723, P < 0.001), measured as days lost per quarter, significantly increased 12 and 24 months after the pandemic's start. This aligns with a notable rise in quarterly incidence at 36 months for both (0.032, P = 0.030 for hepatitis B; 0.040, P < 0.001 for hepatitis C). CONCLUSIONS: The decrease in reported cases could be due to an increase in infection prevention control and containment measures put in place in a pandemic context. However, a delay in the initiation of epidemiological investigations was observed, which could lead to a further increase in incidence in the future.

Long-term results of arthroscopic repair of type II SLAP lesions in sports: assessment of return to pre-injury playing level and critical risk factors for complication.

PURPOSE: The management of isolated SLAP lesions is still debated especially in athletes. Aims of the study were: 1. to analyse our algorithm to treat SLAP lesions starting from the selection of patients for surgery and 2. to correlate the familiarity for diabetes and hypothyroid disorders with post-operative results. METHODS: Seventy-eight patients with isolated SLAP lesion were arthroscopically treated using knotless anchors and microfractures. All patients had a pre-operative and post-operative clinical examination according to Walch-Duplay, Constant, Rowe and Dash scores and interviewed for familiarity to diabetes and hypothyroid disorders. RESULTS: About 68.8% of patients solved pain with rehabilitation. About 29% of patients returned to the sports activities. About 32% of patients were no responder to physiotherapy and were arthroscopically treated. About 53.9% of patients responded excellent, 34.7% good, 3.8% medium and 7.6% poor results according to Walch-Duplay score. The Constant score increased from 64 to 95, the Rowe score from 48 to 96. The outcomes were significantly worse in patients with familiarity for diabetes. CONCLUSIONS: Microfractures and knotless anchor give long-term good results for the treatment of SLAP lesions in athletes. The familiarity for diabetes is an important risk factor that can lead to decreased outcomes.

Inhibition of C5aR1 as a promising approach to treat taxane-induced neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of several antitumor agents resulting in progressive and often irreversible damage of peripheral nerves. In addition to their known anticancer effects, taxanes, including paclitaxel, can also induce peripheral neuropathy by activating microglia and astrocytes, which release pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin 1-beta (IL-1ß), and chemokine (C-C motif) ligand 2 (CCL-2). All these events contribute to the maintenance of neuropathic or inflammatory response. Complement component 5a (C5a)/C5a receptor 1 (C5aR1) signaling was very recently shown to play a crucial role in paclitaxel-induced peripheral neuropathy. Our recent findings highlighted that taxanes have the previously unreported property of binding and activating C5aR1, and that C5aR1 inhibition by DF3966A is effective in preventing paclitaxel-induced peripheral neuropathy (PIPN) in animal models. Here, we investigated if C5aR1 inhibition maintains efficacy in reducing PIPN in a therapeutic setting. Furthermore, we characterized the role of C5aR1 activation by paclitaxel and the CIPN-associated activation of nod-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome. Our results clearly show that administration of the C5aR1 inhibitor strongly reduced cold and mechanical allodynia in mice when given both during the onset of PIPN and when neuropathy is well established. C5aR1 activation by paclitaxel was found to be a key event in the induction of inflammatory factors in spinal cord, such as TNF-α, ionized calcium-binding adapter molecule 1 (Iba-1), and glial fibrillary acidic protein (GFAP). In addition, C5aR1 inhibition significantly mitigated paclitaxel-induced inflammation and inflammasome activation by reducing IL-1ß and NLRP3 expression at both sciatic and dorsal root ganglia level, confirming the involvement of inflammasome in PIPN. Moreover, paclitaxel-induced upregulation of C5aR1 was significantly reduced by DF3966A treatment in central nervous system. Lastly, the antinociceptive effect of C5aR1 inhibition was confirmed in an in vitro model of sensory neurons in which we focused on receptor channels usually activated upon neuropathy. In conclusion, C5aR1 inhibition is proposed as a therapeutic option with the potential to exert long-term protective effect on PIPN-associated neuropathic pain and inflammation.

The data project: a shared approach between stakeholders of the healthcare system in definition of a therapeutic algorithm for inflammatory arthritis.

Rheumatic musculoskeletal diseases or RMD [rheumatoid arthritis (RA) and spondyloarthritis (SpA)] are systemic inflammatory diseases for which there are no biomarkers capable of predicting treatments with a higher likelihood of response in naive patients. In addition, the expiration of the anti-TNF blocking drugs' patents has resulted in the availability of anti-TNF biosimilar drugs with the same efficacy and safety than originators but at significantly reduced prices. To guarantee a personalized therapeutic approach to RMD treatment, a board of rheumatologists and stakeholders from the Campania region, Italy, developed a clinically applicable arthritis therapeutic algorithm to guide rheumatologists (DATA project). The general methodology relied on a Delphi technique forecast to produce a set of statements that summarized the experts' consensus. Selected clinical scenarios were discussed in light of the available evidence, and there were two rounds of voting on the therapeutic approaches. Separate discussions were held regarding rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. The decision-making factors for each disease were clinical presentation, demographics, and comorbidities. In this paper, we describe a virtuous process between rheumatologists and healthcare system stakeholders that resulted in the development of a shared therapeutic algorithm for RMD patients naive to bDMARDs.

Emerging Insights into the Impact of Air Pollution on Immune-Mediated Asthma Pathogenesis.

PURPOSE OF REVIEW: Increases in ambient levels of air pollutants have been linked to lung inflammation and remodeling, processes that lead to the development and exacerbation of allergic asthma. Conventional research has focused on the role of CD4+ T helper 2 (TH2) cells in the pathogenesis of air pollution-induced asthma. However, much work in the past decade has uncovered an array of air pollution-induced non-TH2 immune mechanisms that contribute to allergic airway inflammation and disease. RECENT FINDINGS: In this article, we review current research demonstrating the connection between common air pollutants and their downstream effects on non-TH2 immune responses emerging as key players in asthma, including PRRs, ILCs, and non-TH2 T cell subsets. We also discuss the proposed mechanisms by which air pollution increases immune-mediated asthma risk, including pre-existing genetic risk, epigenetic alterations in immune cells, and perturbation of the composition and function of the lung and gut microbiomes. Together, these studies reveal the multifaceted impacts of various air pollutants on innate and adaptive immune functions via genetic, epigenetic, and microbiome-based mechanisms that facilitate the induction and worsening of asthma.

Colonic transit in patients after anterior resection: prospective, comparative study using single-photon emission CT/CT scintigraphy.

BACKGROUND: Bowel dysfunction after anterior resection is well documented, but its pathophysiology remains poorly understood. No study has assessed whether postoperative variation in colonic transit contributes to symptoms. This study measured colonic transit using planar scintigraphy and single-photon emission CT (SPECT)/CT in patients after anterior resection, stratified according to postoperative bowel function. METHODS: Symptoms were assessed using the low anterior resection syndrome (LARS) score. Following gallium-67 ingestion, scintigraphy was performed at predefined time points. Nine regions of interest were defined, and geometric centre (GC), percentage isotope retained, GC velocity index and colonic half-clearance time (T½ ) determined. Transit parameters were compared between subgroups based on LARS score using receiver operating characteristic (ROC) curve analyses. RESULTS: Fifty patients (37 men; median age 72·6 (range 44·4-87·7) years) underwent planar and SPECT scintigraphy. Overall, 17 patients had major and nine had minor LARS; 24 did not have LARS. There were significant differences in transit profiles between patients with major LARs and those without LARS: GCs were greater (median 5·94 (range 2·35-7·72) versus 4·30 (2·12-6·47) at 32 h; P = 0·015); the percentage retained isotope was lower (median 53·8 (range 6·5-100) versus 89·9 (38·4-100) per cent at 32 h; P = 0·002); GC velocity indices were greater (median 1·70 (range 1·18-1·92) versus 1·45 (0·98-1·80); P = 0·013); and T½ was shorter (median 38·3 (17·0-65·0) versus 57·0 (32·1-160·0) h; P = 0·003). Percentage tracer retained at 32 h best discriminated major LARS from no LARS (area under curve (AUC) 0·828). CONCLUSION: Patients with major LARS had accelerated colonic transit compared with those without LARS, which may help explain postoperative bowel dysfunction in this group. The percentage tracer retained at 32 h had the greatest AUC value in discriminating such patients.

ANTECEDENTES: La disfunción intestinal después de la resección anterior (anterior resection, AR) está bien documentada, pero su fisiopatología sigue siendo poco conocida. Ningún estudio ha evaluado si la variación postoperatoria en el tránsito colónico contribuye a los síntomas. Este estudio midió el tránsito colónico mediante gammagrafía planar con SPECT/CT en pacientes después de una AR, estratificados según la función intestinal postoperatoria. MÉTODOS: Los síntomas se evaluaron mediante el sistema de puntuación del síndrome de resección anterior baja (low anterior resection syndrome, LARS). Después de la administración oral de galio-67, se realizó una gammagrafía en tiempos predefinidos. Se establecieron nueve regiones de interés y se midió/calculó las siguientes variables: (i) centro geométrico (geometric centre, GC); (ii) porcentaje de isótopo retenido; (iii) velocidad del GC; y (iv) semivida de aclaramiento del colon (T1/2). Se compararon los parámetros de tránsito en diferentes subgrupos de pacientes de acuerdo con su puntuación LARS utilizando análisis de curva ROC RESULTADOS: La gammagrafía planar con SPECT se realizó en 50 pacientes con AR seleccionados al azar (37 varones, media de 72,3 años (DE 9,0)). En total, 17 pacientes presentaban un LARS mayor, 9 tenían un LARS menor y 24 no presentaban LARS. En comparación con los pacientes sin LARS, los pacientes con LARS mayor tenían perfiles de tránsito significativamente diferentes: a las 32 horas, (i) los GC fueron mayores (mediana 5,94 (rango 2,35-7,72) versus 4,30 (2,12-6,47), P = 0,015)); (ii) el porcentaje de isótopo retenido fue menor (mediana 53,8% (error estándar de la media 6,5) versus 89,9% (3,4), P = 0,002)); (iii) las velocidades del GC fueron mayores (1,70 (1,18-1,92) versus 1,45 (0,98-1,80), P = 0,013)); y (iv) las semividas T1/2 fueron más cortas (38,3 horas (17,0-65,0) versus 57,0 (32,1-160), P = 0,003)). El porcentaje de isótopo retenido a las 32 horas fue el parámetro que mejor discriminó los pacientes con LARS mayor de los pacientes sin LARS (AUC 0,828). CONCLUSIÓN: Los pacientes con LARS mayor presentaron un tránsito colónico acelerado en comparación con los pacientes sin LARS, lo que puede contribuir a explicar la disfunción intestinal postoperatoria en dichos pacientes. El marcador de porcentaje de isótopo retenido a las 32 horas tenía un valor de AUC más elevado en la discriminación de estos pacientes.

Origin of the New World Plasmodium vivax: Facts and New Approaches.

Malaria is one of the most important human diseases throughout tropical and sub-tropical regions of the world. Global distribution and ample host range have contributed to the genetic diversity of the etiological agent, Plasmodium. Phylogeographical analyses demonstrated that Plasmodium falciparum and Plasmodium vivax follow an Out of Africa (OOA) expansion, having a higher genetic diversity in African populations and a low genetic diversity in South American populations. Modeling the evolutionary rate of conserved genes for both P. falciparum and P. vivax determined the approximate arrival of human malaria in South America. Bayesian computational methods suggest that P. falciparum originated in Africa and arrived in South America through multiple independent introductions by the transatlantic African slave trade; however, in South America, P. vivax could have been introduced through an alternate migratory route. Alignments of P. vivax mitogenomes have revealed low genetic variation between the South American and Southeast Asian populations suggesting introduction through either pre-Columbian human migration or post-colonization events. To confirm the findings of these phylogeographical analyses, molecular methods were used to diagnose malaria infection in archeological remains of pre-Columbian ethnic groups. Immunohistochemistry tests were used and identified P. vivax but not P. falciparum in histologically prepared tissues from pre-Columbian Peruvian mummies, whereas shotgun metagenomics sequencing of DNA isolated from pre-Columbian Caribbean coprolites revealed Plasmodium-homologous reads; current evidence suggests that only P. vivax might have been present in pre-Columbian South America.

Ultra-performance liquid chromatography/multiple reaction monitoring mass spectrometry quantification of trastuzumab in human serum by selective monitoring of a specific peptide marker from the antibody complementarity-determining regions.

RATIONALE: Because of the large molecular weight, the structural complexity and the similarity with endogenous immunoglobulins present in high concentrations, in vivo quantitative studies with therapeutic monoclonal antibodies are particularly challenging. In this work, an UPLC/MRM MS-based methodology is described for the quantification of trastuzumab in human serum by monitoring a novel specific peptide marker located within its heavy chain Complementarity-Determining Region (CDR). METHODS: For maximum sensitivity and selectivity, specific transitions of this diagnostic proteotypic peptide were optimized and monitored at m/z 364.1 â†’ 437.3 (quantitation ion) and m/z 364.1 â†’ 358.0 (confirmation ion). As a proof-of-concept, the methodology was applied to the determination of trastuzumab in human serum over a clinically relevant range from 0.02 to 200 µg/mL. The methodology has been evaluated in terms of specificity, linearity, accuracy, precision, detection and quantitation limits. RESULTS: An excellent linear response has been obtained in the range from 0.036 to 3.6 fmol/µL for the standard peptide and from 0.03 to 285 fmol/µL for the trastuzumab in human serum with typical R2 values of 0.99. The limit of detection (LOD) and limit of quantification (LOQ) are 0.005 fmol/µL and 0.05 fmol/µL, respectively, with mean bias and RSD values of 18% and 1%, respectively, for quality control samples. CONCLUSIONS: The strategy used to set up the UPLC/MRM MS methodology based on monitoring specific peptide markers within CDRs can be potentially applied to the detection and quantification of other humanized or human mAbs in biological fluids. Copyright © 2017 John Wiley & Sons, Ltd.

Effect of lifelong football training on the expression of muscle molecular markers involved in healthy longevity.

PURPOSE: We investigated whether lifelong football training affects the expression of healthy longevity-related muscle molecular markers. METHODS: Biopsies were collected from the vastus lateralis muscle of 10 lifelong football-trained men (68.2 ± 3.0 years) and of 10 active untrained healthy men (66.7 ± 1.3 years). Gene and protein expression was measured by RTqPCR on RNA and by western blotting on protein extracts from muscle biopsies, respectively. RESULTS: The expression of AMPKα1/α2, NAMPT, TFAM and PGC1α, which are markers of oxidative metabolism, and MyHC ß isoform expression was higher in the muscle of football-trained men vs untrained men. Also citrate synthase activity was higher in trained than in untrained men (109.3 ± 9.2 vs 75.1 ± 9.2 mU/mg). These findings were associated with a healthier body composition in trained than in untrained men [body weight: 78.2 ± 6.5 vs 91.2 ± 11.2 kg; body mass index BMI: 24.4 ± 1.6 vs 28.8 ± 4.0 kg m-2; fat%: 22.6 ± 8.0 vs 31.4 ± 5.0%)] and with a higher maximal oxygen uptake (VO2max: 34.7 ± 3.8 vs 27.3 ± 4.0 ml/min/kg). Also the expression of proteins involved in DNA repair and in senescence suppression (Erk1/2, Akt and FoxM1) was higher in trained than in untrained men. At BMI- and age-adjusted multiple linear regression analysis, fat percentage was independently associated with Akt protein expression, and VO2max was independently associated with TFAM mRNA and with Erk1/2 protein expression. CONCLUSIONS: Lifelong football training increases the expression of key markers involved in muscle oxidative metabolism, and in the DNA repair and senescence suppression pathways, thus providing the molecular basis for healthy longevity.

Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy.

Cerebral palsy (CP) is a common, clinically heterogeneous group of disorders affecting movement and posture. Its prevalence has changed little in 50 years and the causes remain largely unknown. The genetic contribution to CP causation has been predicted to be ~2%. We performed whole-exome sequencing of 183 cases with CP including both parents (98 cases) or one parent (67 cases) and 18 singleton cases (no parental DNA). We identified and validated 61 de novo protein-altering variants in 43 out of 98 (44%) case-parent trios. Initial prioritization of variants for causality was by mutation type, whether they were known or predicted to be deleterious and whether they occurred in known disease genes whose clinical spectrum overlaps CP. Further, prioritization used two multidimensional frameworks-the Residual Variation Intolerance Score and the Combined Annotation-dependent Depletion score. Ten de novo mutations in three previously identified disease genes (TUBA1A (n=2), SCN8A (n=1) and KDM5C (n=1)) and in six novel candidate CP genes (AGAP1, JHDM1D, MAST1, NAA35, RFX2 and WIPI2) were predicted to be potentially pathogenic for CP. In addition, we identified four predicted pathogenic, hemizygous variants on chromosome X in two known disease genes, L1CAM and PAK3, and in two novel candidate CP genes, CD99L2 and TENM1. In total, 14% of CP cases, by strict criteria, had a potentially disease-causing gene variant. Half were in novel genes. The genetic heterogeneity highlights the complexity of the genetic contribution to CP. Function and pathway studies are required to establish the causative role of these putative pathogenic CP genes.

Epithelioid angiosarcoma arising in schwannoma of the kidney: report of the first case and review of the literature.

BACKGROUND: Schwannoma and angiosarcoma are infrequent pathologies that have been rarely reported in the kidney. Angiosarcoma is an uncommon malignant tumor presenting a recognizable vascular differentiation. It can develop in any site but the most common locations include the skin, soft tissues, breast, bone, liver, and spleen while renal localization has been very rarely reported in the literature. Schwannoma is a benign peripheral nerve sheath tumor composed of cells with the immunophenotype and ultrastructural features of differentiated Schwann cells. It has a wide anatomical distribution but the most frequent locations include subcutaneous tissues of the extremities and the head and neck region and the retroperitoneal and mediastinal soft tissues. The occurrence of an angiosarcoma in a pre-existing schwannoma is an extremely rare event with <20 cases reported in worldwide literature. In the present study, a renal case of angiosarcoma arising in schwannoma is presented with a detailed review of the pertinent literature. CASE PRESENTATION: A 56-year-old man was admitted with a few days history of lower back pain and hematuria. Abdominal ultrasound showed a mass inside the left renal medulla. Subsequent imaging investigations with computed tomography and magnetic resonance confirmed the presence of the lesion and showed a pulmonary metastasis. CONCLUSIONS: The final histopathological examination led to the diagnosis of epithelioid angiosarcoma arising in a schwannoma. The patient came to death a few months later due to a massive hemothorax. To the best of our knowledge, the present is the first case of an angiosarcoma arising in a schwannoma of the kidney.

Effectiveness of a new method of disinfecting the root canal, using Er, Cr:YSGG laser to kill Enterococcus faecalis in an infected tooth model.

Some lasers have demonstrated to provide effective disinfection when used as adjunctive device to the conventional treatment. The aim of this in vitro study was to determine the effectiveness of the erbium, chromium:yttrium scandium gallium garnet (Er, Cr:YSGG) laser by measuring its bactericidal effect inside the root canal experimentally colonized with Enterococcus faecalis. The laser was tested at different irradiation times (30 and 60 s) and energy of impulses (75 and 25 mJ). A total of 52 single-rooted extracted human teeth were endodontically prepared with rotary instrumentation. All were sterilized and inoculated with a suspension of E. faecalis (105 bacteria/ml). The teeth were randomized into three treatment (group 1, group 2, and group 3) and one control groups. In all groups, teeth were chemically irrigated with 5.25% sodium hypochlorite and 17% ethylenediaminetetraacetic acid. Groups 1 and 2 were also irradiated at 30 and 60 s, respectively, with an Er, Cr:YSGG laser at 75 mJ. Teeth of group 3 were treated with laser for 60 s at 25 mJ. Samples were processed to detect the presence of E. faecalis. For all groups, a bactericidal effect was observed. The use of laser at 75 mJ with an irradiation time of 30 and 60 s eliminated a percentage of 92.3 and 100% of E. faecalis, respectively. In the control group, a reduction of 92.3% was observed. Lower percentage of reduction (46.1%) was obtained in teeth treated with laser at 25 mJ for 60 s. No statistical differences were observed between the groups (P = 0.543, Fisher's exact test). The results indicated a bactericidal effect of Er, Cr:YSGG laser irradiation at the settings used in this study. The highest bactericidal effect of this laser was observed at 60 s of irradiation time, using an energy pulse of 75 mJ.

Non-hormonal treatment of vulvo-vaginal atrophy-related symptoms in post-menopausal women.

In post-menopausal period vulvo-vaginal atrophy (VVA)-related symptoms may seriously affect women's quality of life. Hormonal replacement therapy effectively relieves these symptoms but it is not always safe or accepted, and a non-hormonal treatment is often needed instead. Over a period of 12 weeks, we tested the effect of a twice-a-week vulvo-vaginal application of a hyaluronic acid, AC collagen, isoflavones and vitamins-based cream (Perilei Pausa) on 35 women in post-menopausal period, reporting VVA-related symptoms. After 12 weeks of treatment with Perilei Pausa a significant improvement in vaginal dryness, vulvo-vaginal itching, dyspareunia (P < 0.001), dysuria (P = 0.02), nocturia (P = 0.009) and pollakiuria (P = 0.005) was reported by the women. Colposcopical score assessing the intensity of atrophic colpitis, cervico-vaginal paleness and petechiae was also reduced (P = 0.037, P = 0.016 and P = 0.032, respectively). No significant difference in terms of maturation value of cervico-vaginal epithelium was observed. In conclusion, Perilei Pausa may represent an effective and safe alternative treatment of symptomatic VVA in post-menopausal women.

Safety of rituximab in the routine treatment of rheumatoid arthritis in Italy in patients refractory to anti-TNFa drugs: results from the observational retrospective-prospective RUBINO study.

The paper reports the results from the observational retrospective-prospective RUBINO study conducted in Italy to assess the safety of rituximab in the treatment of rheumatoid arthritis (RA) in routine clinical practice. The percentage of patients who manifested at least one grade 3 or 4 adverse event (AE) assessed by the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v.3) during the observation period (primary objective) was evaluated. The percentage of patients manifesting a severe AE (SAE), clinical response to rituximab treatment, clinical remission according to disease activity score for 28 joints (DAS28) criteria, markers of disease and quality of life were also assessed. Fifty-three Italian rheumatology centers took part in the study. Patients with a diagnosis of RA and inadequate response to anti-tumor necrosis factor b (anti-TNFa) drugs were enrolled. Participating patients had previously received at least one cycle of rituximab, and treatment was still ongoing at the time of recruitment. Out of 205 patients enrolled, 60% manifested no form of AE, 14.2% had at least one grade 3 or 4 AE, and 11.2% patients reported an SAE. The overall percentage of patients manifesting AEs (40%) was lower compared to the DANCER (81% and 85%), REFLEX (85%) and RESET (85% and 69%) studies, but higher than that observed in the CERERRA registry (from 10.2% to 13.9%). This difference may be due to the shorter observation period applied in the CERERRA registry (only 12 months) compared to the RUBINO study (up to 3 years). All parameters of RA activity (erythrocyte sedimentation rate, C-reactive protein, health assessment questionnaire score, DAS28) improved significantly during the study.

In vivo evaluation of periodontal microcirculatory changes associated with endodontic treatment.

AIM: The purpose of this study was to investigate in vivo the gingival microcirculatory changes associated with endodontic treatment using the continuous wave of condensation technique. MATERIALS AND METHODS: Twenty necrotic one canal roots of 20 cooperative patients of both sexes, aged between 20 and 43 years, were selected. All patients were examined by capillaroscopy before, immediately after endodontic treatment, and after 7 days. The last examination was carried out by the same operator, and repeated twice for each examined area: masticatory, buccal and labial mucosa corresponding to the endodontically treated root. All canals were prepared using a simultaneous technique with Ni-Ti files (MTwo files). RESULTS: The images of the masticatory mucosa after root canal obturation showed evident micro-areas of extravasation, with significant bleeding and angio-morphological alterations due to heat. One hour after the endodontic treatment evident extravasation was observed, but a decrease of all altered parameters, was present. After seven days from treatment, in the periodontal tissues, a complete healing was observed. The in vivo evaluation of the vascular pattern during root canal obturation with System B showed that the high temperature in the canal determines visible effects on the vasculature of adjacent sites. It was found that microangiotectonic alterations decrease up to a complete healing after 7 days from treatment. CONCLUSION: All the changes in microcirculation, due to thermal shock of periodontal tissues, are reversible.

Palmitoylethanolamide is a disease-modifying agent in peripheral neuropathy: pain relief and neuroprotection share a PPAR-alpha-mediated mechanism.

Neuropathic syndromes which are evoked by lesions to the peripheral or central nervous system are extremely difficult to treat, and available drugs rarely joint an antihyperalgesic with a neurorestorative effect. N-Palmitoylethanolamine (PEA) exerts antinociceptive effects in several animal models and inhibits peripheral inflammation in rodents. Aimed to evaluate the antineuropathic properties of PEA, a damage of the sciatic nerve was induced in mice by chronic constriction injury (CCI) and a subcutaneous daily treatment with 30 mg kg(-1) PEA was performed. On the day 14, PEA prevented pain threshold alterations. Histological studies highlighted that CCI induced oedema and an important infiltrate of CD86 positive cells in the sciatic nerve. Moreover, osmicated preparations revealed a decrease in axon diameter and myelin thickness. Repeated treatments with PEA reduced the presence of oedema and macrophage infiltrate, and a significant higher myelin sheath, axonal diameter, and a number of fibers were observable. In PPAR- α null mice PEA treatment failed to induce pain relief as well as to rescue the peripheral nerve from inflammation and structural derangement. These results strongly suggest that PEA, via a PPAR- α -mediated mechanism, can directly intervene in the nervous tissue alterations responsible for pain, starting to prevent macrophage infiltration.

Posterior component separation with TAR: lessons learned from our first consecutive 52 cases.

Patients with complex incisional hernia (IH) is a growing and challenging category that surgeons are facing in daily practice and represent indeed a technical challenge for most of them. The posterior component separation with TAR (PCS-TAR) has become the procedure of choice to repair most complex abdominal wall defects, including those with loss of domain, subxiphoid, subcostal, parastomal or after trauma and sepsis treated initially with "open abdomen" and in those scenarios in which the fascia closure was not performed to avoid an abdominal compartment syndrome. Most recent studies showed that the PCS-TAR represents a valid procedure in recurrent IH. The purpose of our study is to evaluate the reproducibility of the PCS-TAR, describing our experience, our surgical technique and the rate of postoperative complications and recurrences in a cohort of consecutive patients. 52 consecutive patients with complex IH, who underwent PCS-TAR at "Betania Hospital and Ospedale del Mare Hospital" in Naples between May 2014 and November 2019 were identified from a prospectively maintained database and reviewed retrospectively. There were 36 males (69%) and 16 females (31%) with a mean age of 57.88 (range 39-76) and Body mass index (BMI kg/m2) of 31.2 (24-45). More than half of patients (58%) were active smokers. Mean defect width was 13.6 cm (range 6-30) and mean defect area was about 267.9 cm2. Mean operative time was 228 min. Posterior fascial closure was reached in all cases, while anterior fascial closure only in 29 cases (56%). Mean hospital stay was 5.7 days. 27% of patients developed minor complications (Clavien-Dindo grade I-II) and one case (1.9%) major complication (Clavien-Dindo III). Seroma was registered in 23% of cases. SSI was reported to be 3.8% with no deep wound infection. Recurrence rate was 1.9% in a mean follow-up of 28 months. In Univariate analysis Bio-A surface > 600 cm2 and drain removal at discharge were significantly associated with major complications, while in a multivariate analysis only Bio-A surface > 600 cm2 was related. Considering univariate analysis for recurrences, number of drains, SSO, Clavien-Dindo score > 2 and defect area were significantly associated with recurrence, while in a multivariate analysis no variables were related. PCS-TAR is an indispensable tool in managing complex ventral hernias associated with a low rate of SSO and recurrence. Tobacco use, obesity and comorbidities cannot be considered absolute contraindications to PCS-TAR. Peri and postoperative management of complications and drainages have an impact on short term outcomes. Based on these outcomes, posterior component separation with transversus abdominis release has become our method of choice for the management of patients with complex ventral hernia requiring open hernia repair in selected patients.

KCTD1 is a new modulator of the KCASH family of Hedgehog suppressors.

The Sonic Hedgehog (Hh) signal transduction pathway plays a critical role in many developmental processes and, when deregulated, may contribute to several cancers, including basal cell carcinoma, medulloblastoma, colorectal, prostate, and pancreatic cancer. In recent years, several Hh inhibitors have been developed, mainly acting on the Smo receptor. However, drug resistance due to Smo mutations or non-canonical Hh pathway activation highlights the need to identify further mechanisms of Hh pathway modulation. Among these, deacetylation of the Hh transcription factor Gli1 by the histone deacetylase HDAC1 increases Hh activity. On the other end, the KCASH family of oncosuppressors binds HDAC1, leading to its ubiquitination and subsequent proteasomal degradation, leaving Gli1 acetylated and not active. It was recently demonstrated that the potassium channel containing protein KCTD15 is able to interact with KCASH2 protein and stabilize it, enhancing its effect on HDAC1 and Hh pathway. KCTD15 and KCTD1 proteins share a high homology and are clustered in a specific KCTD subfamily. We characterize here KCTD1 role on the Hh pathway. Therefore, we demonstrated KCTD1 interaction with KCASH1 and KCASH2 proteins, and its role in their stabilization by reducing their ubiquitination and proteasome-mediated degradation. Consequently, KCTD1 expression reduces HDAC1 protein levels and Hh/Gli1 activity, inhibiting Hh dependent cell proliferation in Hh tumour cells. Furthermore, analysis of expression data on publicly available databases indicates that KCTD1 expression is reduced in Hh dependent MB samples, compared to normal cerebella, suggesting that KCTD1 may represent a new putative target for therapeutic approaches against Hh-dependent tumour.

MRI-derived radiomics to guide post-operative management of glioblastoma: Implication for personalized radiation treatment volume delineation.

Background: The glioblastoma's bad prognosis is primarily due to intra-tumor heterogeneity, demonstrated from several studies that collected molecular biology, cytogenetic data and more recently radiomic features for a better prognostic stratification. The GLIFA project (GLIoblastoma Feature Analysis) is a multicentric project planned to investigate the role of radiomic analysis in GB management, to verify if radiomic features in the tissue around the resection cavity may guide the radiation target volume delineation. Materials and methods: We retrospectively analyze from three centers radiomic features extracted from 90 patients with total or near total resection, who completed the standard adjuvant treatment and for whom we had post-operative images available for features extraction. The Manual segmentation was performed on post gadolinium T1w MRI sequence by 2 radiation oncologists and reviewed by a neuroradiologist, both with at least 10 years of experience. The Regions of interest (ROI) considered for the analysis were: the surgical cavity ± post-surgical residual mass (CTV_cavity); the CTV a margin of 1.5 cm added to CTV_cavity and the volume resulting from subtracting the CTV_cavity from the CTV was defined as CTV_Ring. Radiomic analysis and modeling were conducted in RStudio. Z-score normalization was applied to each radiomic feature. A radiomic model was generated using features extracted from the Ring to perform a binary classification and predict the PFS at 6 months. A 3-fold cross-validation repeated five times was implemented for internal validation of the model. Results: Two-hundred and seventy ROIs were contoured. The proposed radiomic model was given by the best fitting logistic regression model, and included the following 3 features: F_cm_merged.contrast, F_cm_merged.info.corr.2, F_rlm_merged.rlnu. A good agreement between model predicted probabilities and observed outcome probabilities was obtained (p-value of 0.49 by Hosmer and Lemeshow statistical test). The ROC curve of the model reported an AUC of 0.78 (95% CI: 0.68-0.88). Conclusion: This is the first hypothesis-generating study which applies a radiomic analysis focusing on healthy tissue ring around the surgical cavity on post-operative MRI. This study provides a preliminary model for a decision support tool for a customization of the radiation target volume in GB patients in order to achieve a margin reduction strategy.

Different inflammatory stimuli in the footpad of mice influence the kinetics of resident peritoneal cells.

OBJECTIVES: Evidence from the literature that inflammation is a systemic biological phenomenon prompted us to investigate whether inoculation of different irritants to the footpad of mice might influence the kinetics of resident peritoneal cells. METHODS: Mice were inoculated in the footpad at different time intervals with Mycobacterium bovis bacillus Calmette-Guerin (BCG), Ehrlich ascitic tumor cells or lipopolysaccharide (LPS), and resident peritoneal cells were analyzed by flow cytometry. RESULTS: The results indicate that different stimuli induced different responses in resident peritoneal cells. FoxP3 positive regulatory T cells increased drastically in number after BCG inoculation. Conversely, tumor cell inoculation induced a decrease in FoxP3-positive T cells in the peritoneal cavity, although this effect was not statistically significant. Results also show that cells from the paw migrate to the popliteal lymph node and to the peritoneal cavity. Yet, there are cells in the peritoneal cavity that migrate to the popliteal lymph node. CONCLUSION: These data show that cells from the peritoneal cavity are influenced by pathologies in remote regions of the animal. How this novel phenomenon influences overall immune responses, courses of infection and tumor growth are open to further investigation.