Evaluation of Hearing Functions in Children with Celiac Disease and the Effect of Gluten-free Diet on these Functions.

OBJECTIVE: The present study aims to investigate the potential impact of celiac disease (CD) on hearing functions and assess the effect of a gluten-free diet (GFD) on this condition. MATERIALS AND METHODS: The study included 55 children with CD (110 ears) and 25 healthy controls (50 ears) matched for age and gender. The CD group was divided into adherent (n = 31) and nonadherent (n = 24) to GFD. Participants underwent tympanometry and pure tone audiometry assessments covering frequencies from 500 to 4000 Hz. RESULTS: Patients with CD showed significantly higher air and bone conduction hearing averages compared to the control group at frequencies of 500, 1000, 2000, and 4000 Hz for air conduction, and at 500 Hz for bone conduction (P < 0.05). Celiac patients, those who fully adhered to GFD, had notably higher air conduction hearing averages at 500, 2000, and 4000 Hz compared to healthy controls (P < 0.05). However, there was no difference in bone conduction hearing averages between the two groups. In contrast, celiac patients who did not comply with GFD had statistically significantly higher air and bone conduction hearing averages than the control group (P < 0.05), at frequencies of 500, 1000, and 4000 Hz for air conduction, and at 500 and 1000 Hz for bone conduction (P < 0.05). CONCLUSIONS: The study suggests that nonadherence to GFD may elevate the risk of hearing loss in children with CD. As a result, it is recommended to conduct hearing screenings for children with CD and underscore the importance of complying with GFD to mitigate further detrimental effects on hearing functions.

Exploring the influence of placing bi-directional E-glass fibers as protective layer under a CAD-CAM resin composite on the fracture pattern.

OBJECTIVES: To investigate the influence of the presence and position of bidirectional E-glass fibers under a CAD-CAM resin composite on the fracture pattern evaluated both after quasi-static mechanical loading and after fatigue. METHODS: Rectangular specimens (10 mm-long, 5 mm-large and 4.2 mm-thick) were prepared and divided into four groups (n = 30/group). The control group (C-Group) consisted of a 4.2 mm-thick layer of monolithic CAD/CAM resin composite resin (Cerasmart, GC). In the 3 other groups including the placement of a fiber layer (F-Groups), the CAD/CAM resin composite layer was reduced to 3-, 2- and 1-mm thickness (F3-, F2- and F1-Groups, respectively). Two bonded layers of bidirectional E-glass FRC (Dentapreg, ADM A.S.) were bonded underneath and a light-curable resin composite base (Gaenial Posterior, GC) was then added to reach a total thickness of 4.2 mm for all samples. In each group, half of the specimens (n = 15) were submitted to quasi-static mechanical loading to failure in a universal testing machine. The other half (n = 15) was subjected to cyclic isometric stepwise loading until failure or completion of 105000 cycles (5000 cycles at 500 N, followed by five stages of 20000 cycles at 750 N, 1000 N, 1250 N, 1500 N, and 1750 N). The data were analyzed by Weibull statistics for quasi-static loading, and by the Kaplan-Meier product limit estimation procedure after fatigue. All fractured specimens were studied using light and electron microscopy techniques, and the types of fracture were determined. RESULTS: For quasi-static mechanical loading, significant differences were observed for Weibull modulus and characteristic strength between groups, with values ranging from 10.8 to 22.4 for the former and from 2336.6 to 2974.7 for the latter. Also, survival after stepwise fatigue revealed statistically significant differences between groups (p < 0.05), the lowest values of cycles before failure being observed for F1-Group - Median = 61223 (50415; 65446) - as compared to the other groups - C-Group: Median = 89005 (86189; 98195); F3-Group: Median = 85198 (77279; 87860); F2-Group: Median = 89306 (87454; 97024). Both in quasi-static loading and after fatigue, the observation of fracture modes revealed major differences. While all fractures were vertical (split) in C-Group, the majority of the specimens in F-Groups presented some degree of horizontal deflection of the crack. In all deviated fractures, fractographic analysis confirmed a toughening effect of the fiber layer. SIGNIFICANCE: The present in vitro work tends to show that the fracture pattern of CAD-CAM resin composites is favorably affected by the presence and position of an underlying bidirectional E-glass fiber layer. The placement of E-glass fibers under a CAD-CAM resin composite may therefore represent an interesting strategy to reduce the risk of catastrophic restoration failure, which could be integrated in the development of the new generation of indirect materials, possibly in 3D-printing approaches.

Optical Property Stability of Light-Cured versus Precured CAD-CAM Composites.

Objective: The aim of this study was to evaluate the optical property changes after staining of precured (PC) and light-cured (LC) composites. Materials and Methods: Specimens were prepared using different LC composites (GrandioSO-Voco, Filtek Z350-3M/ESPE, Opallis-FGM, and Kalore-GC) and four PC blocks (Grandio Blocs-Voco, Lava Ultimate-3M ESPE, Brava Block-FGM, and Cerasmart-GC) from the same manufacturers (n = 20). Baseline color, gloss, translucency, and fluorescence were evaluated. The staining protocol was performed for 15 days, and the final optical properties were reevaluated. Results: The changes in each property were calculated (ΔGloss, ΔTranslucency, ΔFluorescency, ΔE ∗ 00). Data were analyzed by ANOVA and Tukey's test (α = 5%). Changes in all properties were observed after staining for all materials, with darkening and reduction of gloss, fluorescence, and translucency. Nonsignificant differences were observed between the light-cured and precured materials of the same manufacturer for ΔG and ΔT, but significant differences existed for ΔF and ΔE ∗ 00. For ΔF, the only significant differences were observed between Brava Block and Opallis (smaller). For ΔE ∗ 00, only the light-cured composites GrandioSO and Z350 showed significantly less change than the corresponding blocks. Precured composites were affected the same way as light-cured ones by the staining in relation to the reduction of gloss and translucency. Conclusion: A higher reduction in fluorescence was observed for only one brand of block and was similar for the others. The two brands of light-cured materials showed less staining, while for the others, the staining was similar. The effects of staining vary according to the composite formulation.

The clinical and economic burden of proximal femur periprosthetic fractures.

BACKGROUND: The number of hip replacements is constantly and progressively increasing, resulting in an increase in periprosthetic fractures. The main aim of this study is to analyze costs and outcomes of surgical treatment for those fractures. MATERIALS AND METHODS: A retrospective study was performed on periprosthetic proximal femur fracture presented a single-level I trauma center. Medical records were reviewed in terms of demographic data, diagnosis (according to Vancouver classification), type of surgical treatment, hospitalization length and follow-up. Patients were interviewed about number of consultations after discharge, medications and physiotherapy sessions. Clinical outcome was evaluated with WOMAC score at the last follow-up, and patient health status was evaluated with the EQ5D5L score pre-trauma and at the last follow-up. Patients were divided into two groups according to surgical treatment: reduction and internal fixation alone and revision plus fixation. A further group was also considered: patients underwent a Girdlestone procedure. Global costs for each group were calculated. RESULTS: We initially recruited 117 patients, 17 of them were lost at follow-up. Furthermore, 19 patients (19%) died during the follow-up, and 81 of them were therefore included in the study. Mean follow-up was 26.5 months. Mean postoperative WOMAC score was 39.44, and EQ5D5L score was 9.12 for the preoperative period and 12.35 at the last follow-up. A significant worsening of clinical conditions was found comparing the period before fracture to the last follow-up (p < 0.01). Quality of life after surgery resulted to be poor or fair in 40% of the patients at a mean follow-up of 26.5 months. No significant differences between groups were found according to patients' health status. Mean global costs for mayor surgeries were 18,822 Euros; mean costs for fixation alone were 17,298 Euros while for fixation and revision were 20,966 Euros, but no statistically difference was found between these two groups. Mean cost for Girdlestone group was 12,664 Euros. CONCLUSIONS: In proximal femur periprosthetic fractures, either fixation or revision plus fixation presents high costs but patients' postoperative quality of life is poor.

Tumorigenic effect mediated by ROS/eicosanoids and their regulation on TP53 expression in a murine mammary gland adenocarcinoma.

The aim of this study was to investigate the in vivo and in vitro effects of dietary ω-6 and ω-3 polyunsaturated fatty acids (PUFAs) and their derivatives on the expression of TP53 and their relationship with cellular proliferation and death in a murine mammary adenocarcinoma model. BALB/c mice were divided in three diet groups: chia oil (ChO) rich in ω-3, corn oil (CO) rich in ω-6/ω-3 and safflower oil (SO) rich in ω-6 and subcutaneously inoculated with LMM3 mammary tumor cell line. Results demonstrated that diets with higher concentration of omega-6 PUFAs induced an increment of linoleic and arachidonic acid on tumor cell membranes increasing ROS liberation, 12(S)-HHT generation, TP53, Ki67 expression and cell proliferation. However, diets enriched with high content in omega-3 PUFAs induced higher tumor cell apoptosis and tumor infiltration of CD3+ lymphocytes, lowest cell viability and proliferation. Dietary omega-3 PUFAs nutritional intervention can be used as a potential preventative strategy to inhibit the molecular signaling pathways involved in the mammary tumor growth process as the TP53.

Dentin Cross-linking Effect of Carbodiimide After 5 Years.

Carbodiimide (EDC)-based dentin primers preserve hybrid layer (HL) integrity. However, aging >1 y has not been investigated. The present study examined whether the cross-linking effect of EDC was reflected in dentin bond strength, endogenous enzymatic activity, and the chemical profile of the HL after 5-y aging in artificial saliva. Noncarious human third molars (N = 42) were cut to expose middle/deep coronal dentin and treated as follows: group 1, dentin etched with 35% H3PO4, pretreated with a 0.3M aqueous EDC primer for 1 min and restored with XP Bond (Dentsply Sirona); group 2, as in group 1 but without EDC pretreatment; group 3, Clearfil SE Bond (Kuraray-Noritake) primer applied to dentin surface, followed by EDC pretreatment as in group 1 and application of bond; group 4, as in group 3 without EDC pretreatment. After composite buildup, the specimens were cut into sticks or slabs, depending on the experiment. All tests were performed at baseline (T0) and after 5 y of aging (T5) in artificial saliva at 37 °C. Microtensile bond strength (µTBS) was tested at a crosshead speed of 1 mm/min until failure. Endogenous enzymatic activity was investigated with in situ zymography. The chemical profile of HL was determined via Raman spectroscopy. Three-way analysis of variance and post hoc Tukey test were used to analyze µTBS and in situ zymography data (α = 0.05). EDC pretreatment and aging significantly influenced µTBS and in situ zymography results (P < 0.05). Higher bond strength and lower gelatinolytic activity were identified in the EDC-treated groups at T5 (P < 0.05), especially in the etch-and-rinse groups. Raman spectra revealed less defined amide III peaks in control specimens at T5. The EDC cross-linking effect persisted in the HL for 5 y in terms of bond strength, collagen structure preservation, and dentinal enzyme silencing.

5-year retrospective evaluation of direct composite restorations in orthodontically treated patients.

OBJECTIVES: In patients affected by dimensional discrepancy between size of anterior maxillary and mandibular teeth, orthodontic therapy could be necessary to solve occlusal problems. However, anterior restorations are indicated to finalize the aesthetic aspect of the therapy. The aim of the present retrospective clinical study was to evaluate the long-term outcomes of direct additive composite restorations performed to correct anterior teeth discrepancies persisting after orthodontic treatment. METHODS: Patients with dimensional teeth discrepancy, subjected to a combined orthodontic-restorative treatment, between January 2009 and January 2019, were recalled for the present retrospective evaluation and divided in two groups according to the restoration performed: G1) diastema closure; G2) tooth shape modification. All patients, after ortho therapy, were subjected to a standardized restorative rehabilitation of the anterior area. All restorations were performed by a single experienced operator employing the same materials. During recall visits, two calibrated examiners evaluated the restorations and recorded USPHS data. Kaplan-Meier estimator and Cox-regression analysis were performed. Statistical significance was set for p < 0.05. RESULTS: 53 patient were included, with a total of 169 restoration (G1:110;G2:59). The mean study time period was 5 year (ranging from 6 month to 10 years). The overall survival rate of additive restoration was 2,59% (G1:2,07%; G2:0,47 p < 0.05). Chipping of the material was the most frequent adverse event (G1:13,64%; G2:1,69), followed by composite wear (G1:9,09%; G2:5,17). CONCLUSIONS: Based on the obtained results, good clinical performances were shown at a 5-year interval. A low number of failures were collected and most of them were classified as reparable. Only few cases needed complete reintervention. CLINICAL SIGNIFICANCE: Showing that a direct approach in restoring anterior teeth for diastema closure or shape modification is a valid alternative in terms of durability and aesthetics to more invasive procedure such as indirect restorations.

Tridimensional Evaluation of the Interfacial Gap in Deep Cervical Margin Restorations: A Micro-CT Study.

CLINICAL RELEVANCE: Using a material that optimizes marginal seal when using a margin elevation technique to manage deep class II cavities should enhance clinical outcomes. SUMMARY: Objectives: The purpose of this laboratory study was to perform a tridimensional interfacial gap evaluation of class II cavities with enamel and dentin cervical margins, before and after cyclic fatigue, restored with different nanohybrid resin composites.Methods and Materials: Standardized class II cavities were performed on 48 intact maxillary premolars, placing the mesial cervical margin 1 mm above the cement-enamel junction (CEJ) and the distal cervical margin 1 mm below the CEJ. Specimens were treated with two-step self-etch adhesive (Clearfil SE Bond2) and divided into six groups according to the restoration technique. Microcomputed Tomography imaging was executed before and after 1,000,000 cycles of chewing simulation at 50 N. Tridimensional interfacial gaps, expressed as cubic millimeters, were analyzed through a standardized software flowchart (Mimics). Data were analyzed with a two-way analysis of variance and Tukey post hoc tests (α=0.05).Results: Restoration technique (p=0.001) and chewing simulation (p=0.00001) significantly influenced interfacial gap on dentin but not on enamel. The post hoc test showed that, on dentin margins, flowable resins had a lower gap at baseline but a higher gap after chewing simulation, especially when a 2-mm-thick layer was applied, compared with nanohybrid and bulk-fill composites.Conclusions: Based on the obtained results, no differences in interfacial gap volume were found on enamel margins. On dentin margins, flowable resins showed better marginal seal at baseline, but they seem to be more prone to interfacial degradation during chewing simulation than traditional composites.

Longevity of class 2 direct restorations in root-filled teeth: A retrospective clinical study.

OBJECTIVES: To evaluate retrospectively the longevity of endodontically treated teeth restored with direct resin composite without cusp coverage, with or without the insertion of fibre posts. The null hypothesis was that direct restorations with fibre posts perform better than those without fibre posts. METHODS: Patients recruited for this study were treated in the Department of Cariology and Operative Dentistry, University of Turin, between 2008 and 2011. In total, 247 patients with 376 root treated posterior teeth, restored with direct resin composite, were recalled for a control visit. Only second-class cavities were considered. Two groups were defined based on the absence (Group A) or presence (Group B) of fibre post. Failures and complications, such as periodontal failure, endodontic failure, tooth extraction, root fracture, post fracture, post debonding, replacement of restoration, crown displacement, and coronal-tooth fracture, were noted. Functional restoration quality was evaluated following the modified USPHS criteria. Data were evaluated statistically with ANOVA. RESULTS: Group A consisted of 128 patients with 178 restorations (88 premolars, 90 molars) with a median follow-up of 34.44 months. Group B consisted of 119 patients with 198 teeth (92 premolars, 106 molars) with a median follow-up of 35.37 months. Direct restorations with fibre posts were statistically significantly more functional (95.12% success) than those without fibre posts (80% success) because of less marginal discolouration, better marginal integrity, and higher restoration integrity. CONCLUSIONS: The null hypothesis was accepted because direct post-endodontic restorations with fibre posts performed better than restorations without posts after 3 years of masticatory function. CLINICAL SIGNIFICANCE: An evaluation of the longevity of post endodontic direct restoration would seem to enhance the fiber post insertion within a composite restoration to reduce clinical failures.

Pimecrolimus vs. tacrolimus for the topical treatment of unresponsive oral erosive lichen planus: a 8 week randomized double-blind controlled study.

BACKGROUND: Oral lichen planus (OLP) is a chronic inflammatory disease, affecting nearly 1-2% of the population; Proposed therapies are usually symptomatic and numerous drugs have been used, but recently, it has been published that there is insufficient evidence to support the effectiveness of any specific treatment as being superior. To the best of our knowledge, direct evaluation of the efficacy of topically applied pimecrolimus and tacrolimus in the treatment of atrophic-erosive OLP, refractory to topical steroids, is still lacking. OBJECTIVES: To assess the efficacy and safety of topical calcineurin inhibitors for unresponsive OLP. An 8 week randomized, double-blind controlled trial, followed by a 6 month follow-up period. Patients were treated with either pimecrolimus 1% cream or tacrolimus 0.1% ointment, both mixed with an equivalent amount of 4% hydroxyethyl cellulose gel. The medications were to be applied twice daily for 2 months. Each patient was examined at the beginning of therapy, and then every 2 weeks during the treatment and every 3 months of follow-up. Main outcome measures were: (i) to compare the effectiveness of topically applied pimecrolimus and tacrolimus; (ii) to evaluate which is more cost-effective; (iii) to determine which drug is faster in reducing signs and symptoms and (iv) which gives the longest remission. RESULTS: Thirty patients were involved in the study. Both drugs were effective at inducing clinical improvement, with no statistical difference. Pimecrolimus creams revealed a significantly better stability of the therapeutic effectiveness (P = 0.031). CONCLUSION: Both medications would currently appear to be a treatment of choice for patients with unresponsive atrophic-erosive OLP. Pimecrolimus seemed to be more effective in providing long-term resolution of signs and symptoms. Future efforts are however needed to obtain more objective evidence of the benefit of these medications in the treatment of immunologically mediated oral mucosal lesion.

Primers on molecular pathways - lipoxygenases: their role as an oncogenic pathway in pancreatic cancer.

Different evidence supports a functional role of enzymes involved in lipid metabolic pathways, such as lipoxygenases (LOXs) and their metabolite derivatives, in carcinogenesis. LOX enzymes catalyze the dioxygenation of arachidonic acid into hydroxyperoxyeicosatetraenoic acids, which is followed by their conversion to their corresponding eicosanoids as hydroxyeicosatetraenoic acids, leukotrienes, lipoxins and hepoxilins, which in turn act as cellular messengers. Subcellular LOX enzyme localization varies according to the LOX and cellular type regulating different cell functions. LOX enzymes or their products may exert their biological effects in different modes, either intracellular or in other cells. Numerous clinical studies on expression of LOXs in human tumors as well as in animal models indicate different roles of distinct LOX isoforms in carcinogenesis. In fact, different LOXs exhibit either protumorigenic or antitumorigenic activities and modulate the tumor response in a tissue-specific manner. Moreover, the LOX pathways are involved in the spread and metastasis of several cancers, including pancreas, through the activation of several cellular signaling pathways which modify gene expression affecting cellular proliferation, survival, migration and extracellular matrix production. In this review we focus on the important role and different mechanisms of action of LOX pathways in the regulation of pancreatic cancer initiation and progression. A novel approach for pancreatic cancer chemoprevention would involve targeting LOX activities, alone or in combination with other pathways as a major anticancer strategy.

The role of early radiological studies after gastric bariatric surgery.

BACKGROUND: The authors investigated early radiological findings after gastric surgery for morbid obesity to evaluate their usefulness in avoiding complications or facilitating treatment. MATERIAL AND METHODS: 413 patients underwent gastric bariatric surgery: 327 had vertical banded gastroplasty (VBG), 55 Roux-en-Y gastric bypass (RYGBP), 22 adjustable silicone gastric banding (ASGB), and 9 biliopancreatic diversion (BPD). A radiological upper gastrointestinal investigation employing water-soluble contrast medium was performed in each patient between the 2nd and 8th postoperative day. Several techniques were employed to assess different radiological findings related to the anatomic modifications after the bariatric surgery. RESULTS: In VBGs, delayed emptying was found in 10 patients (3%), gastric leak in 3 patients (0.9%), vertical suture breakdown in 1 patients (0.3%), and a wide pouch in 4 patients (1.2%). In RYGBP, a leak was detected in 2 patients (3.6%), delayed emptying in 2 (3.6%), and a wide pouch in 5 (9.1%). ASGB required band enlargement for stomal stenosis in 6 patients (27.2%). Temporary delayed emptying from stomal stenosis was also observed in 2 BPDs (22.2%). Overall complications were 35/413 (8.2%). Two cases of gastric leak after VBG were reoperated. Stomal stenosis after ASGB were treated by percutaneous band deflation; other cases were medically treated until complete healing. CONCLUSIONS: Early radiological study after gastric bariatric surgery is advisable, since it detected postoperative complications (gastric perforation, stomal stenosis, etc.) and modified the clinical approach. As the interpretation of these radiographs is often difficult, involving different projections or patient's positions or other technical managements, surgeons and radiologists must interact and be knowledgable.

A randomised phase II study of oxaliplatin alone versus oxaliplatin combined with 5-fluorouracil and folinic acid (Mayo Clinic regimen) in previously untreated metastatic colorectal cancer patients.

The aim of this study was to examine the efficacy and safety of both oxaliplatin as a single agent and oxaliplatin in combination with dailyx5 bolus 5-fluorouracil and folinic acid (5-FU/FA, Mayo clinic regimen) in the first-line treatment of metastatic colorectal cancer (CRC) patients. 73 advanced CRC patients were randomised to receive either oxaliplatin 85 mg/m(2) every 2 weeks (35 patients), or the same treatment combined with 5-FU 425 mg/m(2)/day and FA 20 mg/m(2)/dayx5 days every 4 weeks (38 patients). Treatment was continued until disease progression or unacceptable toxicity. All patients had documented inoperable disease and no previous chemotherapy for advanced disease. Based on the investigators' assessment of best response, objective response rate was 9% (95% confidence interval (CI) 2-24%) in the oxaliplatin arm, and 45% (95% CI 27-64%) in the oxaliplatin+5-FU/FA arm. Median progression-free survival (PFS) was 2 months (95% CI 1.7-2.4 months) in the oxaliplatin arm and 3.9 months (95% CI 2.9-5 months) in the oxaliplatin+5-FU/FA arm. Severe neutropenia was seen in 23% of patients in the oxaliplatin+5-FU/FA arm, and none in the oxaliplatin arm. There were two treatment-related deaths, both in the oxaliplatin+5-FU/FA arm. In the oxaliplatin+5-FU/FA arm, severe diarrhoea, vomiting and stomatitis were seen in 34, 14 and 14% of the patients, respectively. In conclusion, oxaliplatin at a dose of 85 mg/m(2) given every 2 weeks was well tolerated and has limited activity in metastatic CRC, while the combination of this treatment with the full-dose Mayo clinic regimen (5-FU bolus 425 mg/m(2)/day+FA 20 mg/m(2)/dayx5 days every 4 weeks), although active, was unfeasible due to a high level of myelosuppression and gastrointestinal toxicity. Alternative lower dosing or other regimens are to be explored to ascertain the value of bolus 5-FU/FA combined with oxaliplatin.

Evaluation of carboxymethylcellulose, hydroxypropylmethylcellulose, and aluminum hydroxide as potential carriers for rhBMP-2.

Conventional iliac crest nonvascularized corticocancelous bone grafts and bone flaps have been used to treat bony defects. However, these treatments have some limitations, namely, the availability of donor tissue, donor site morbidity, difficulty to shape the bone flap to the defect, and complexity of the surgery. The bone morphogenetic protein (rhBMP-2) is osteoinductive. However, its implantation requires a matrix (carrier) in order to define the shape of the resulting bone and to retain the protein at the site for the time required for induction to occur. When the ideal carrier is found, an unlimited supply of material would be available for all applications where bone is needed. In this in vitro study, we evaluated the suitability of some potential carriers for rhBMP-2 by measuring the alkaline phosphatase (ALP) activity of fibroblast cultures. Either rhBMP-2 or sodium carboxymethylcellulose significantly increased the ALP activity, when used alone. When sodium carboxymethylcellulose was combined with rhBMP-2, there was an increase in the ALP activity, but lower than those obtained when the products were used alone. Hydroxypropylmethylcellulose alone did not affect ALP activity. However, the combination of rhBMP-2 with hydroxypropylmethylcellulose did not increase the ALP activity, despite the presence of rhBMP-2. Aluminium hydroxide proved to be an unsuitable rhBMP-2 adsorbent.

The control of progesterone receptor expression in MCF-7 breast cancer cells: effects of estradiol and sex hormone-binding globulin (SHBG).

Estradiol controls the gene transcription and expression of many proteins in breast cancer cells, like the progesterone receptor, PR, that is up-regulated by the hormone. Moreover, estradiol is one of the crucial factors inducing the proliferation of breast cancer cells. Sex Hormone-Binding Globulin (SHBG), the plasma carrier for both estradiol and androgens, inhibits the estradiol-induced growth of MCF-7 cells (estrogen-dependent breast cancer cells), through its membrane receptor (SHBG-R), cAMP and PKA. The anti-estrogenic effect of SHBG, which has been described only as far as cell proliferation is concerned, could also play a meaningful role in the estradiol control of other factors in breast cancer cells. In the present study, the effect of SHBG on the estradiol control of PR expression (both mRNA and protein) and function (receptor binding capacity) in MCF-7 cells was examined. SHBG inhibited the estradiol-induced up-regulation of PR mRNA as well as protein level and function. Moreover, the effect of SHBG on estradiol control of PR expression and function was showed to be specific and mediated by PKA. The intermediacy of PKA in the PR expression control, together with the observation that it is effective in the condition in which the SHBG receptor is activated, supports the hypothesis that the anti-estrogenic effect of SHBG could be receptor-mediated. The ability of SHBG to inhibit estradiol action in a specific way in estrogen-dependent breast cancer cells has, therefore, to be taken into account for the development of future therapeutic strategies.

Single-agent gemcitabine in pretreated patients with non-small-cell lung cancer: results of an Argentinean multicentre phase II trial.

The activity and mild toxicity profile of single-agent gemcitabine therapy in untreated (chemonaive) patients with non-small-cell lung cancer (NSCLC) is well documented. This phase II trial was conducted to determine the objective tumour response rate and toxicity profile of single-agent gemcitabine in pretreated patients with NSCLC. Patients with histological evidence of advanced NCSLC stage IIIB or IV; at least one prior chemotherapy regimen including a platinum or taxane analogue; an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2; clinically measurable disease; adequate bone marrow reserve; and adequate renal function; received 1000 mg m(-2) gemcitabine administered over 30 min on days 1, 8 and 15 of a 28-day cycle defined as 3 weekly treatments followed by 1 week of rest. Twenty-nine patients were evaluated for efficacy and 32 for toxicity. One patient achieved a complete response and five patients had a partial response resulting in a total response rate of 20.6% (95% confidence interval (CI) 6-34). Median response duration was 7 months (range 4-11 months). Twelve (41%) patients reached stable disease after two cycles of therapy and 11 (38%) patients had disease progression. Median progression-free survival time was 3 months and median overall survival time was 5.5 months. Toxicity was generally mild (grades 0-2). Severe (grade 3 or 4) haematological toxicities included grade 3 anaemia in one patient and grade 3 thrombocytopenia in two patients. Severe non-haematological toxicities included one patient each with grade 3 liver transaminase elevations, nausea/vomiting and diarrhoea. This study confirms the activity and safety of single-agent gemcitabine in pretreated patients with advanced NSCLC who are refractory or sensitive to first-line therapy.

Sex hormone-binding globulin, its membrane receptor, and breast cancer: a new approach to the modulation of estradiol action in neoplastic cells.

The role of human Sex Hormone-Binding Globulin (SHBG), the plasma carrier of sex steroids, and its membrane receptor, SHBG-R, in estrogen-dependent breast cancer has been investigated in our laboratory in the past few years. SHBG-R is expressed in MCF-10 A cells (not neoplastic mammary cells), MCF-7 cells (breast cancer, ER positive) and in tissue samples from patients affected with ER positive breast cancer, but not in estrogen-insensitive MDA-MB 231 cells. The SHBG/SHBG-R interaction, followed by the binding of estradiol to the complex protein/receptor, causes a significant increase of the intracellular levels of cAMP, but does not modify the amount of estradiol entering MCF-7 cells. The estradiol-induced proliferation of MCF-7 cells is inhibited by SHBG, through SHBG-R, cAMP and PKA. Similarly, the proliferation rate of tissue samples positive for SHBG-R was significantly lower than the proliferation rate of negative samples. SHBG and SHBG-R could thus trigger a 'biologic' anti-estrogenic pathway. In order to get a more detailed knowledge of this system, we first examined the frequence of the reported mutated form of SHBG in 255 breast cancer patients. The mutated SHBG is characterized by a point mutation (Asp 327 --> Asn) causing an additional N-glycosylation site, which does not affect the binding of steroids to SHBG. The frequence of the mutation was significantly higher (24.5%) in estrogen-dependent breast cancers than in healthy control subjects (11.6%). This observation confirms the close relationship between SHBG and estrogen-dependent breast cancer and suggests that the mutation could modify SHBG activity at cell site. Lastly, the possibility of using SHBG to modulate the estradiol action in breast cancer was further studied by transfecting MCF-7 cells with an expression vector carrying the SHBG cDNA (study in collaboration with G.L. Hammond). Transfected cells are able to produce significant amount of SHBG in their medium, but their SHBG-R is reduced to undetectable levels. The SHBG produced by transfected MCF-7 cells is, however, able to inhibit estradiol-induced proliferation of MCF-7 cells expressing a functional receptor. Thus, the local production of SHBG obtained with transfection could be a useful tool to control cell growth in estrogen-dependent breast cancer.

[Free flaps in the reconstruction of head and neck. Clinical experience]. / Retaehos livres na reconstrução da cabeça e pescoço. Experiência clínica.

The reconstruction of head and neck defects, due to trauma, tumor resection or other, begins with a careful assessment of the patient and the respective defect. Ideally, it ends with the successful reconstructive procedure that optimally restores form and function to the patient. Free flaps have often been used as a last resort reconstructive option in the head and neck because of the need for added technical skill, a longer operating time and a perception of poor reliability. This study reviews our experience with forty-eight patients submitted to microvascular reconstructive procedures. Twelve different kinds of free flaps have been involved as the preferred choice for free flap reconstruction of a specific defect of the head and neck. The latissimus dorsi flap was used for scalp and skull reconstruction, whereas the serratus anterior or rectus abdominis free flaps were used for the reconstruction of complex defects of the middle third of the face. The radial forearm flap and the free jejunal transfer have become the preferred choices for intraoral and pharyngo-esophageal reconstruction, respectively. Good results were obtained with both functional and social rehabilitation. There were three flap losses probably due to thrombosis of the microvascular anastomosis. There was no surgical mortality. The indications for each free flap are discussed.

[Cutaneous reconstruction at the leg and foot level. Experience in 277 clinical cases]. / Reconstrução cutânea ao nivel da perna e do pe. Experiência em 227 casos clínicos.

The authors present their clinical experience of leg and foot reconstruction with 227 clinical cases. Based on these cases the authors analyse the use of 18 musculocutaneous, 53 axial, 72 septocutaneous and 84 free flaps, totalling 29 different kinds of flaps performed. Although no definitive conclusions can be drawn about which are the best flaps for foot and leg reconstruction, the preferential options are pointed out.

Sex steroid binding protein receptor (SBP-R) is related to a reduced proliferation rate in human breast cancer.

In the last years, an increasing amount of studies described a membrane receptor for the Sex Steroid Binding Protein (SBP) on several androgen-estrogen dependent tissues. One of the suggested biological roles of the interaction between SBP and its receptor seems to be a negative control of the E2 induced proliferation of human breast cancer cells through the cAMP pathway. In the present work, SBP membrane receptor was evaluated on human breast cancer specimens with a radio-binding assay. Each tissue sample was also evaluated for ER and PGR status. Cytosol Thymidine Kinase levels were measured in tissue samples in order to evaluate cell proliferation rate. SBP binding to membranes of ER +/PGR + samples was time and temperature dependent, specific and at high affinity. In addition, SBP recognized on breast cancer membranes two sites at different affinity, as previously described for other human tissues and cultured cells. Membrane SBP-R was detected in a significantly higher number of samples positive for both ER and PGR than in negative samples. SBP-R positive samples showed a significantly lower proliferation rate than SBP-R negative samples as demonstrated by TK activity. The present study contains evidences for the existence of a specific membrane receptor for SBP in breast cancer sample membranes and the presence of SBP-R seems to be strictly related to a lower proliferation rate of the sample.