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Purpose: Secretory breast cancer (SBC) is one of the rarest breast cancer (BC), representing the majority of BC in childhood. Nevertheless, it elicits a lot of interest both for the peculiar morphology and the characteristic genetic features. Currently, there is no consensus on optimal treatment strategy. Therefore, it is useful to report every case in order to establish treatment algorithms.Methods: We describe the case of a 6-year-old boy diagnosed with a SBC, with peculiar genomic and immunohistochemical features. Moreover, we carried out a review of the literature in order to analyze the present state of knowledge about this rare entity.Results: To the best of our knowledge, there are only 120 cases published in literature, only 32 in males and only 2 younger than 6 years. Furthermore, this one had peculiar genomic and immunohistochemical features. Indeed, even if SBC expresses basal-cell markers, our patient had a triple-negative tumor expressing both basal and luminal cell markers. Furthermore, the boy’s genomic profile revealed not only positivity for the typical SBC’s translocation t(12;15), but also for a 3q28 duplication, found in his father (healthy) and paternal grandfather (with a previous BC). None were positive for BRCA mutation. This locus includes only one gene encoding for a growth factor recently linked to Early Infantile Epileptic Encephalopathy-47 and Idiopathic ventricular tachycardia. Even if the literature does not provide evidence of a pathogenic role it is not possible to exclude a cancer-predisposing activity.Conclusions: SBC is a rare type of BC, characterized by triple-negative features with an unexpectedly good prognosis. More data are needed to fully understand the behavior of this cancer and genomic profiling could be helpful in improving its diagnosis and management. [ABSTRACT FROM AUTHOR]

We evaluated the accuracy of a new scale of surgical difficulty for the extraction of impacted mandibular third molars, which includes consideration of previously underestimated variables. Two hundred patients with impacted third molars were enrolled, and a preoperative clinical and radiographic assessment of difficulty was made by an oral surgeon using the new index. Five oral surgeons with similar degrees of experience then evaluated the surgical difficulty during operation. The kappa test and weighted kappa were used to evaluate the level of agreement between the preoperative and postoperative evaluations. This was 0.73, which indicated a substantial concordance between the preoperative and postoperative assessments of difficulty indicated by the new scale. The linear weight of kappa was 0.8 and the quadratic weight 0.87. We recommend this new scale of surgical difficulty for the extraction of impacted third molars for use in clinical practice. [ABSTRACT FROM AUTHOR]

Immunotherapy is increasingly used in advanced non-small-cell lung cancer (NSCLC), offering a significant anti-tumor response, as well as causing rising immune-related adverse effects. The incidence of immune checkpoint inhibitor-induced myocarditis-myositis-myasthenia gravis is increasing and particularly concerning due to its high mortality rate. Prompt recognition, diagnosis, and management are crucial. A 40-year-old patient, diagnosed with stage IV non-oncogene addicted lung adenocarcinoma, with nivolumab-ipilimumab-chemotherapy as first-line treatment, developed a rare myocarditis-myositis-myasthenia gravis overlap syndrome. Following the treatment, the patient presented with flu-like symptoms and chest pain and subsequently transferred to the cardiac intensive care unit. The physical examination revealed a visual acuity deficit, diplopia, ophthalmoparesis, ptosis, mydriasis, dysphagia, dyspnea, headache, nausea, dry mouth, asthenia, myalgia, and muscle weakness. Imaging and laboratory tests confirmed the triad, showing an elevation of hs-cTnI and CK and positive results for anti-SAE1 and anti-PL-7 Abs. ECG revealed ST segment elevation and RBBB. The echo showed hyperechogenicity of the inferolateral wall, pericardial detachment, and thickening. The cardiac MRI demonstrated hypokinesia, edema, subepicardial LGE, and pericardial effusion. Muscle biopsy revealed muscle fiber necrosis and regeneration with B and T lymphocytic endomysial inflammatory infiltrate and expression of MHC-I. Treatment with oral prednisone, pyridostigmine, and IV Igs was started due to poor clinical response followed by methylprednisolone. Despite stopping immunotherapy, the patient continued to benefit from it, as highlighted on subsequent re-evaluation CT scans by partial disease response, and as the patient was in complete remission, we decided to resume chemotherapy by omitting immunotherapy. At the radiological control following the four cycles of double CHT and during CHT maintenance, there was a further reduction of the disease. This report aims to raise awareness among physicians about these serious side effects. A multidisciplinary approach led to clinical improvement and early intervention, optimizing patient outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mariniello, Arrivi, Tufano, Lauletta, Moro, Tini, Garibaldi, Giusti and Mazzuca.)

Maxillary sinus augmentation is one of the most predictable procedures for the rehabilitation of the posterior maxilla. The current overview aimed to summarize the findings provided by systematic reviews (SRs) and meta-analyses on the effectiveness of autologous platelet concentrates (APCs) in sinus lift and to assess the methodological quality of the included SRs. Three electronic databases have been explored. SRs and meta-analyses addressing the effectiveness of APCs in sinus lift technique were included. Clinical, radiographic and histomorphometric findings were considered for APCs as solely grafting materials and APCs in combination with biomaterials. Outcomes were implant survival rate (ISR), implant stability (IS), implant failure (IF), postoperative complications, histomorphometric findings, radiographic bone gain, bone volume and bone density. The methodological quality of the included SRs was assessed using the updated version of "A Measurement Tool to Assess Systematic Review" (AMSTAR-2). Thirty SRs were included. The methodological quality of the included reviews ranged from critically low (3 studies) to high (9 studies). The included SRs showed favorable clinical outcomes, short-term new bone formation and no biological complications when APCs were used both as solely graft material or in combination with other biomaterials. However, no significant additional effects in the long-term period were observed. APCs did not add any further positive effects compared to the physiological healing derived by the natural blood clot. The current overview of SRs highlighted the need for high-quality SRs evaluating the role of APCs in sinus lift though network meta-analyses, in order to identify the most powerful material for sinus lift augmentation. The use of APCs improves the healing of soft tissues and the postoperative quality of life in the short-term period. Thus, its application can be recommended.

Missense mutations in the uromodulin (UMOD) gene cause autosomal dominant tubulointerstitial kidney disease (ADTKD), one of the most common monogenic kidney diseases. The unknown impact of the allelic and gene dosage effects and fate of mutant uromodulin leaves open the gap between postulated gain-of-function mutations, end-organ damage and disease progression in ADTKD. Based on two prevalent missense UMOD mutations with divergent disease progression, we generated Umod C171Y and Umod R186S knock-in mice that showed strong allelic and gene dosage effects on uromodulin aggregates and activation of ER stress and unfolded protein and immune responses, leading to variable kidney damage. Deletion of the wild-type Umod allele in heterozygous Umod R186S mice increased the formation of uromodulin aggregates and ER stress. Studies in kidney tubular cells confirmed differences in uromodulin aggregates, with activation of mutation-specific quality control and clearance mechanisms. Enhancement of autophagy by starvation and mTORC1 inhibition decreased uromodulin aggregates. These studies substantiate the role of toxic aggregates as driving progression of ADTKD-UMOD, relevant for therapeutic strategies to improve clearance of mutant uromodulin., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Background: Uromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown., Methods: We conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing., Results: Two genome-wide significant signals were identified for uUMOD: a novel locus ( P 1.24E-08) over the KRT40 gene coding for KRT40, a type 1 keratin expressed in the kidney, and the UMOD-PDILT locus ( P 2.17E-88), with two independent sets of single nucleotide polymorphisms spread over UMOD and PDILT . Two genome-wide significant signals for uUCR were identified at the UMOD-PDILT locus and at the novel WDR72 locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the KRT40 locus, were similar for both uUMOD and uUCR. KRT40 colocalized with uromodulin and modulating its expression in thick ascending limb (TAL) cells affected uromodulin processing and excretion., Conclusions: Common variants in KRT40 , WDR72 , UMOD , and PDILT associate with the levels of uromodulin in urine. The expression of KRT40 affects uromodulin processing in TAL cells. These results, although limited by lack of replication, provide insights into the biology of uromodulin, the role of keratins in the kidney, and the influence of the UMOD-PDILT locus on kidney function., (Copyright © 2022 by the American Society of Nephrology.)

ATP7B is a hepato-specific Golgi-located ATPase, which plays a key role in the regulation of copper (Cu) homeostasis and signaling. In response to elevated Cu levels, ATP7B traffics from the Golgi to endo-lysosomal structures, where it sequesters excess copper and further promotes its excretion to the bile at the apical surface of hepatocytes. In addition to liver, high ATP7B expression has been reported in tumors with elevated resistance to platinum (Pt)-based chemotherapy. Chemoresistance to Pt drugs represents the current major obstacle for the treatment of large cohorts of cancer patients. Although the mechanisms underlying Pt-tolerance are still ambiguous, accumulating evidence suggests that lysosomal sequestration of Pt drugs by ion transporters (including ATP7B) might significantly contribute to drug resistance development. In this context, signaling mechanisms regulating the expression of transporters such as ATP7B are of great importance. Considering this notion, we investigated whether ATP7B expression in Pt-resistant cells might be driven by transcription factor EB (TFEB), a master regulator of lysosomal gene transcription. Using resistant ovarian cancer IGROV-CP20 cells, we found that TFEB directly binds to the predicted coordinated lysosomal expression and regulation (CLEAR) sites in the proximal promoter and first intron region of ATP7B upon Pt exposure. This binding accelerates transcription of luciferase reporters containing ATP7B CLEAR regions, while suppression of TFEB inhibits ATP7B expression and stimulates cisplatin toxicity in resistant cells. Thus, these data have uncovered a Pt-dependent transcriptional mechanism that contributes to cancer chemoresistance and might be further explored for therapeutic purposes.

Purpose: To compare the effect of trehalose 3%/hyaluronic acid 0.15% vs hyaluronic acid 0.15% eyedrops in reducing ocular surface inflammation after cataract surgery., Setting: Perugia, Italy., Design: Randomized, prospective study., Methods: Patients with healthy ocular surface were enrolled. Tear break-up time (TBUT), Schirmer test, corneal fluorescein staining (CFS), ocular surface disease index (OSDI) and in vivo confocal microscopy (IVCM) were performed preoperatively and at 1 months, 4 months, and 8 months postoperatively. Patients were randomly assigned to receive trehalose 3%/hyaluronic acid 0.15% eyedrops (Group A), hyaluronic acid 0.15% eyedrops (Group B), or no treatment (Group C)., Results: 98 patients were randomized as follows: 33 in Group A, 33 in Group B, and 32 in Group C. Schirmer test increased at 1-month follow-up in Group A and unchanged in Groups B and C. TBUT and CFS increased at 1-month follow-up in Group A and after 8 months in Groups B and C. OSDI score decreased at 1-month follow-up in Group A and at in Groups B and C. IVCM showed a reduction in the number of nerve fibers of the subbasal nerve plexus at 1 month in all groups and progressively increased to preoperative levels at 4 months in Group A, and at 8 months in Groups B and C. Tortuosity and reflectivity of subbasal plexus progressively decreased to became significant at 4-month follow-up in Group A whereas increased at 1-month follow-up and become normal at 8-month follow-up in Groups B and C. Langerhans cells and activated stromal keratocytes were higher in Groups B and C throughout the follow-up with a significantly lower density of hyperreflective stromal cells in Group A., Conclusions: Trehalose 3%/hyaluronic acid 0.15% eyedrops were effective in reducing inflammation and dry-eye symptoms., (Copyright © 2021 Published by Wolters Kluwer on behalf of ASCRS and ESCRS.)

Purpose: Prospective, randomised, open-label, comparative study to evaluate efficacy of trehalose/sodium hyaluronate eye drops for post-operative discomfort and tear film stability in patients undergoing cataract surgery., Methods: Patients with healthy ocular surface, subclinical, or mild dry eye were enrolled. Tear breakup time (TBUT), Schirmer test, dry eye symptoms, corneal fluorescein staining (CFS), and ocular surface disease (OSDI) evaluation were performed pre-operatively and at two and four weeks after surgery. Patients were assigned to receive trehalose/sodium hyaluronate eye drops b.i.d (Group A), or 0.9% unpreserved sodium chloride eye drops b.i.d for 4 weeks (Group B)., Results: One hundred and thirty-five patients were randomised, 66 patients in Group A (73.2 ± 4.5 years) and 69 patients in Group B (74.3 ± 3.8 years), 60.8% females. Fifteen patients (8 Group A) were lost at follow-up. Pre-operatively, no between-group differences were observed, and TBUT increased in Group A between the pre-operative and 2 and 4 week evaluations and was higher in group A than in Group B at 4 weeks. Schirmer test and CFS showed an improvement only in Group A four weeks post-operatively. In Group A an improvement was observed after two and four weeks in foreign body and puncture sensation, whilst a difference in blinking discomfort was observed after four weeks. In Group B we observed an improvement in puncture sensation two and four weeks after surgery. Mean OSDI scores differences between the two groups were significant at four weeks., Conclusions: Trehalose/sodium hyaluronate eye drops were effective in reducing signs and symptoms of dry eye and improving tear film stability., (© 2021. The Author(s).)

Aim: The phosphorylation level of the furosemide-sensitive Na + -K + -2Cl - cotransporter (NKCC2) in the thick ascending limb (TAL) is used as a surrogate marker for NKCC2 activation and TAL function. However, in mice, analyses of NKCC2 phosphorylation with antibodies against phosphorylated threonines 96 and 101 (anti-pT96/pT101) give inconsistent results. We aimed (a) to elucidate these inconsistencies and (b) to develop a phosphoform-specific antibody that ensures reliable detection of NKCC2 phosphorylation in mice., Methods: Genetic information, molecular biology, biochemical techniques and mouse phenotyping was used to study NKCC2 and kidney function in two commonly used mouse strains (ie 129Sv and in C57BL/6 mice). Moreover, a new phosphoform-specific mouse NKCC2 antibody was developed and characterized., Results: Amino acids sequence alignment revealed that C57BL/6 mice have a strain-specific five amino acids deletion (ΔF97-T101) in NKCC2 that diminishes the detection of NKCC2 phosphorylation with previously developed pT96/pT101 NKCC2 antibodies. Instead, the antibodies cross-react with the phosphorylated thiazide-sensitive NaCl cotransporter (NCC), which can obscure interpretation of results. Interestingly, the deletion in NKCC2 does not impact on kidney function and/or expression of renal ion transport proteins as indicated by the analysis of the F2 generation of crossbred 129Sv and C57BL/6 mice. A newly developed pT96 NKCC2 antibody detects pNKCC2 in both mouse strains and shows no cross-reactivity with phosphorylated NCC., Conclusion: Our work reveals a hitherto unappreciated, but essential, strain difference in the amino acids sequence of mouse NKCC2 that needs to be considered when analysing NKCC2 phosphorylation in mice. The new pNKCC2 antibody circumvents this technical caveat., (© 2021 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Containment measures adopted to reduce the spread of coronavirus disease 2019 (COVID-19) have produced a general perception of job insecurity. Dentists have been highly affected by such measures, as they represent an easy source of contagion. As perceived job insecurity is associated with psychological distress and Italian dentists have been highly affected by the COVID-19 outbreak in terms of potential financial loss and the risk of being infected, this study aimed at assessing whether the fear of COVID-19 moderated the effect of perceived job insecurity on depressive symptoms. This cross-sectional online study has included 735 Italian dentists recruited during the lockdown and ranging in age from 27 to 70 years old (495 men and 240 women). A quantile regression model with an inference based on the median and with an interaction term between the fear of COVID-19 and perceived job insecurity has been used to estimate the hypothesized associations. The results indicated that both perceived job insecurity and fear of COVID-19 were positively associated with depressive symptoms, and that the effect of perceived job insecurity on depressive symptoms was weaker among those with a low fear of COVID-19. The findings may inform public health policies for dentists in relation to reducing the risk of developing negative mental health outcomes.

One of the goals of immediate breast reconstruction (IBR) is to satisfy the patient's outcome. Recent studies therefore tended to focus on the patient's perception of the care and on the impact on quality of life using patients-reported-outcome-measures (PROMs), able to measure the health status directly without the clinician's interposition. We present a preliminary prospective study on 333 patients who underwent mastectomy with IBR in a two-year period, in a single Italian centre, using a dedicated PROMs, the BREAST-Q™, to determine the patient's satisfaction. We studied two groups of IBR: Group A (two-step with tissue-expander) and Group B (one-step: prosthesis/mesh) and conducted a pre- and post-operative comparison for each group to evaluate score-gain over time, and a group-score comparison to determine whether differences were significant between reconstruction types. Two-hundred-and-nine were actually enrolled and 132 completed all the questionnaires. The response rate was 62.8% and the compliance rate (completion of all the questionnaires) was 63.1%. In both groups all the analyzed domains worsened comparing the pre and post-operative period; the differences were statistically significant only for physical and sexual-wellbeing. In the comparison between the two groups, none of the detected differences reached the statistical significance. According to our experience, we can state that PROMs could improve the health concept redefining the variables to be monitored even if data is still insufficient to draw any definitive conclusion. PROMs can help surgeons and patients decide the most appropriate surgery for a particular patient-profile and to identify those who require further support., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Tumor resistance to chemotherapy represents an important challenge in modern oncology. Although platinum (Pt)-based drugs have demonstrated excellent therapeutic potential, their effectiveness in a wide range of tumors is limited by the development of resistance mechanisms. One of these mechanisms includes increased cisplatin sequestration/efflux by the copper-transporting ATPase, ATP7B. However, targeting ATP7B to reduce Pt tolerance in tumors could represent a serious risk because suppression of ATP7B might compromise copper homeostasis, as happens in Wilson disease. To circumvent ATP7B-mediated Pt tolerance we employed a high-throughput screen (HTS) of an FDA/EMA-approved drug library to detect safe therapeutic molecules that promote cisplatin toxicity in the IGROV-CP20 ovarian carcinoma cells, whose resistance significantly relies on ATP7B. Using a synthetic lethality approach, we identified and validated three hits (Tranilast, Telmisartan, and Amphotericin B) that reduced cisplatin resistance. All three drugs induced Pt-mediated DNA damage and inhibited either expression or trafficking of ATP7B in a tumor-specific manner. Global transcriptome analyses showed that Tranilast and Amphotericin B affect expression of genes operating in several pathways that confer tolerance to cisplatin. In the case of Tranilast, these comprised key Pt-transporting proteins, including ATOX1, whose suppression affected ability of ATP7B to traffic in response to cisplatin. In summary, our findings reveal Tranilast, Telmisartan, and Amphotericin B as effective drugs that selectively promote cisplatin toxicity in Pt-resistant ovarian cancer cells and underscore the efficiency of HTS strategy for identification of biosafe compounds, which might be rapidly repurposed to overcome resistance of tumors to Pt-based chemotherapy.

Background and Purpose: Human malignant hyperthermia (MH) syndrome is induced by volatile anaesthetics and involves increased levels of cystathionine β-synthase (CBS)-derived H 2 S within skeletal muscle. This increase contributes to skeletal muscle hypercontractility. K v 7 channels, expressed in skeletal muscle, may be a molecular target for H 2 S. Here, we have investigated the role of K v 7 channels in MH., Experimental Approach: Skeletal muscle biopsies were obtained from MH-susceptible (MHS) and MH-negative (MHN) patients. Immunohistochemistry, RT-PCR, Western blot, and in vitro contracture test (IVCT) were carried out. Development and characterization of primary human skeletal muscle cells (PHSKMC) and evaluation of cell membrane potential were also performed. The persulfidation state of K v 7 channels and polysulfide levels were measured., Key Results: K v 7 channels were similarly expressed in MHN and MHS biopsies. The IVCT revealed an anomalous contractility of MHS biopsies following exposure to the K v 7 channel opener retigabine. Incubation of negative biopsies with NaHS, prior to retigabine addition, led to an MHS-like positive response. MHS-derived PHSKMC challenged with retigabine showed a paradoxical depolarizing effect, compared with the canonical hyperpolarizing effect. CBS expression and activity were increased in MHS biopsies, resulting in a major polysulfide bioavailability. Persulfidation of K v 7.4 channels was significantly higher in MHS than in MHN biopsies., Conclusions and Implications: In skeletal muscle of MHS patients, CBS-derived H 2 S induced persulfidation of K v 7 channels. This post-translational modification switches the hyperpolarizing activity into depolarizing. This mechanism can contribute to the pathological skeletal muscle hypercontractility typical of MH syndrome., Linked Articles: This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc., (© 2019 The British Pharmacological Society.)

Purpose: To evaluate efficacy of a microemulsion of fatty acids of the ω-3 series on the regeneration of the sub-epithelial corneal nerve plexus in patients with keratoconus after epi-off cross-linking., Methods: In this prospective study, we recruited 40 patients, 18 females, mean age 28 years (range 22-37), who were randomly divided in two groups. Group A, 20 patients, after cross-linking were treated with a microemulsion of fatty acids of the ω-3 series. Group B were treated with hyaluronic acid (0.15%)-based tear substitute. Nerve tortuosity, reflectivity and density were examined with in vivo confocal microscopy. Ocular surface disease index (OSDI) questionnaire at the preoperative and at each follow-up visit (1, 3 and 6 months) after treatment was completed., Results: No significant difference between the two groups was noted at 1 month in terms of nerve density and OSDI. A statistically significant difference between the two groups was detected at 3 months in terms of nerve fibers density (6 ± 0.82 in Group A and 1 ± 0.51 in Group B, P = 0.0001). Reflectivity and tortuosity of the fibers did not show significant differences between the two groups at any time point. At 1 month, OSDI average value in group A and in group B was 31.5 ± 1.94 and 30 ± 1.96, at 3 months 13 ± 1.71 and 28 ± 1.83, and at 6 months 10.5 ± 1.87 and 9.0 ± 1.81, respectively., Conclusion: The use of a microemulsion of fatty acids appears to ensure a faster regeneration of nerve fibers in patients undergoing epi-off cross-linking.

Objectives: Presence of clinical attachment loss on the distal aspect to the second molar may be associated with malposition of the third molar. The aim of this study was to evaluate the reduction of clinical attachment loss at the distal aspect of the second molar after third molar extraction and application of leukocyte- and platelet-rich fibrin (L-PRF)., Method and Materials: Eighteen subjects with a clinical attachment loss on the distal site to the second molar associated with impacted third molar in both sides of the jaw were recruited for the study. For each subject the teeth were randomly allocated in test and control groups. After surgical removal of the impacted third molar, the L-PRF was inserted in the fresh alveolar socket of test sites; in the control sites no graft was inserted after extraction. Full-mouth plaque score, full-mouth bleeding score, clinical attachment level (CAL), probing depth, and gingival recession were assessed at baseline and 6 months later., Results: After 6 months, mean CAL change was 1.99 ± 1.18 mm in the test group and 1.15 ± 1.01 mm in the control group; probing depth change was 1.33 ± 0.87 mm in the test group and 0.50 ± 0.63 mm in the control group. Statistically significant differences (P < .05) were observed between groups in terms of CAL and probing depth changes. No differences were found in gingival recession changes., Conclusion: Within the limits of the present study, the sites treated by means of application of L-PRF after impacted third molar extraction showed better results in terms of CAL gain and probing depth reduction when compared with control sites.

Background & Aims: Wilson disease (WD) is an inherited disorder of copper metabolism that leads to copper accumulation and toxicity in the liver and brain. It is caused by mutations in the adenosine triphosphatase copper transporting β gene (ATP7B), which encodes a protein that transports copper from hepatocytes into the bile. We studied ATP7B-deficient cells and animals to identify strategies to decrease copper toxicity in patients with WD., Methods: We used RNA-seq to compare gene expression patterns between wild-type and ATP7B-knockout HepG2 cells exposed to copper. We collected blood and liver tissues from Atp7b -/- and Atp7b +/- (control) rats (LPP) and mice; some mice were given 5 daily injections of an autophagy inhibitor (spautin-1) or vehicle. We obtained liver biopsies from 2 patients with WD in Italy and liver tissues from patients without WD (control). Liver tissues were analyzed by immunohistochemistry, immunofluorescence, cell viability, apoptosis assays, and electron and confocal microscopy. Proteins were knocked down in cell lines using small interfering RNAs. Levels of copper were measured in cell lysates, blood samples, liver homogenates, and subcellular fractions by spectroscopy., Results: After exposure to copper, ATP7B-knockout cells had significant increases in the expression of 103 genes that regulate autophagy (including MAP1LC3A, known as LC3) compared with wild-type cells. Electron and confocal microscopy visualized more autophagic structures in the cytoplasm of ATP7B-knockout cells than wild-type cells after copper exposure. Hepatocytes in liver tissues from patients with WD and from Atp7b -/- mice and rats (but not controls) had multiple autophagosomes. In ATP7B-knockout cells, mammalian target of rapamycin (mTOR) had decreased activity and was dissociated from lysosomes; this resulted in translocation of the mTOR substrate transcription factor EB to the nucleus and activation of autophagy-related genes. In wild-type HepG2 cells (but not ATP7B-knockout cells), exposure to copper and amino acids induced recruitment of mTOR to lysosomes. Pharmacologic inhibitors of autophagy or knockdown of autophagy proteins ATG7 and ATG13 induced and accelerated the death of ATP7B-knockout HepG2 cells compared with wild-type cells. Autophagy protected ATP7B-knockout cells from copper-induced death., Conclusion: ATP7B-deficient hepatocytes, such as in those in patients with WD, activate autophagy in response to copper overload to prevent copper-induced apoptosis. Agents designed to activate this autophagic pathway might decrease copper toxicity in patients with WD., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Purpose: To compare corneal thickness (CT) measurements obtained with SP3000P specular microscope and Pentacam in eyes screened to undergo refractive surgery (RS)., Methods: In this prospective study, a non-randomized consecutive series of 73 healthy eyes (age range: 14-78 years; mean=38.4±14.9) underwent CT measurement with both Oculus Pentacam and Topcon SP3000P specular microscope to assess their suitability to undergo corneal RS., Results: CT measurements with SP3000P ranged from 451 to 609 μs (mean 523.1±34.4 μs). The measurements obtained with Pentacam ranged at the corneal apex from 477 to 672 μs (mean 558.9±38.9 μs), at the pupil center from 477 to 672 μs (mean 557.9±38.9 μs) and at the thinnest point from 474 to 669 μs (mean 551.1±39.4 μs). CT measurements showed a good correlation but a statistically significant difference at the pupil center (mean -34.9±14.6 μs, R(2)=0.860, p<0.001), at the apex (mean -35.9±14.9 μs, R(2)=0.856, p<0.001) and at the thinnest point (mean -32±14.8 μs, R(2)=0.862, p<0.001). The calculated regression formulas were: y=0.816x+66.94 for the apex, y=0.819x+66.07 for the pupil center and y=0.810x+73.13 for the thinnest point; where y is the CT measured with the SP3000P and x is the measurement obtained with the Oculus Pentacam., Conclusions: Our results suggest that SP3000P measures thinner corneas compared to the Pentacam and that the correcting factor we identified should be applied to make comparisons between these two devices., (Copyright © 2014 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.)

Objective: To compare mallet osteotomes with screwable osteotomes determining benign paroxysmal positional vertigo (BPPV) following the osteotome closed sinus floor elevation procedure., Materials and Methods: This triple-blind randomized controlled trial involved 196 patients affected by edentulous atrophic ridges (107 males and 89 females; mean age 62.05±7.10; age range 49-79 years), requiring an osteotome closed sinus floor elevation procedure. Patients were randomly allocated to either a mallet-osteotomes group (Group 1, n=98) or a screwable osteotomes group (Group 2, n=98). Two different surgeons, blind to the study, performed the closed sinus lift procedure according to the blocks allocation. A complete post-surgical examination, including the Dix-Hallpike maneuver, was performed on 196 patients before and after surgery. The diagnosis of BPPV was supported by the existence of ageotropic nystagmus concurrent with vertigo., Results: Three patients of Group 1 (3/98-3.06%) showed a BPPV of the posterior semicircular canal omo-lateral to the implanted side 1 or 2 days after the surgical procedure, which was promptly solved using the Epley re-positioning maneuver., Conclusions: Preparation of implant beds with osteotome and mallet transmits percussive and vibratory forces capable of detaching the otoliths from their normal location; moreover, the patient's surgical head position favors the displacement of otoliths into the posterior semicircular canal. Implant surgeons should be aware of this possible complication following closed sinus lift procedure and patients should always be informed before undergoing surgery., (© 2010 John Wiley & Sons A/S.)

Purpose: The aim of this study was to assess the anatomy of the mandibular lingual foramen (MLF) and its linked canals (mandibular lingual vascular canals - MLVC), describing their frequency, diameter, location, and course., Materials and Methods: One hundred and fourteen computed tomography (CT) images of the mandible (57 male and 57 female; mean age 44.70±12.53; age range 13-75 years, were evaluated. The CT sections were obtained on axial plane by using a bone reconstruction algorithm and then processed with dedicated software (Dentascan), with a standard protocol., Results: 103 patients (90.35%) had at least one lingual vascular canal and 52 (45.61%) had multiple (two or three) canals. The typical locations of MLVC were the midline of the mandible (median lingual canal [MLC]). The mean diameter of the lingual canals in the midline (MLC) was 0.8mm±0. The direction of MLC progresses in an anterior and slightly caudal sense., Conclusions: Dental CT examination easily demonstrates the presence, position, direction and size of the lingual foramen and of the lingual vascular canals of the mandible. Radiologists and oral surgeons should be aware of these canals and their importance, in order to prevent bleeding complications during implants placement and other surgical procedures., (Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.)