Monocyte-to-platelets ratio (MPR) at diagnosis is associated with inferior progression-free survival in patients with mantle cell lymphoma: a multi-center real-life survey.

Mantle cell lymphoma (MCL) pathogenesis is strongly related to the role of the tumor immune microenvironment (TIME) in which MCL cells proliferate. TIME cells can produce growth signals influencing MCL cells' survival and exert an antitumoral immune response suppression. The activity of TIME cells might be mirrored by some ratios of peripheral blood cell subpopulations, such as the monocyte-to-platelet ratio (MPR). We reviewed the clinical features of 165 consecutive MCL patients newly diagnosed and not eligible for autologous stem cell transplantation (both for age or comorbidities) who accessed two Italian Centers between 2006 and 2020. MPR was calculated using data obtained from the complete blood cell count at diagnosis before any cytotoxic treatment and correlated with PFS. Univariate analysis showed that MPR ≥ 3 was associated with inferior PFS (p = 0.02). Multivariate analysis confirmed that MPR ≥ 3, LDH > 2.5 ULN, and bone marrow involvement were significant independent variables in predicting PFS. For these reasons, MPR ≥ 3 seems the most promising prognostic factor in patients with MCL, and it could be considered a variable in new predictive models.

Mucin Expression Profiles in Ulcerative Colitis: New Insights on the Histological Mucosal Healing.

A structural weakness of the mucus barrier (MB) is thought to be a cause of ulcerative colitis (UC). This study aims to investigate the mucin (MUC) composition of MB in normal mucosa and UC. Ileocolonic biopsies were taken at disease onset and after treatment in 40 patients, including 20 with relapsing and 20 with remitting UC. Ileocolonic biopsies from 10 non-IBD patients were included as controls. Gut-specific MUC1, MUC2, MUC4, MUC5B, MUC12, MUC13, MUC15, and MUC17 were evaluated immunohistochemically. The promoters of mucin genes were also examined. Normal mucosa showed MUC2, MUC5B, and MUC13 in terminal ileum and colon, MUC17 in ileum, and MUC1, MUC4, MUC12, and MUC15 in colon. Membranous, cytoplasmic and vacuolar expressions were highlighted. Overall, the mucin expression was abnormal in UC. Derangements in MUC1, MUC4, and MUC5B were detected both at onset and after treatment. MUC2 and MUC13 were unaffected. Sequence analysis revealed glucocorticoid-responsive elements in the MUC1 promoter, retinoic-acid-responsive elements in the MUC4 promoter, and butyrate-responsive elements in the MUC5B promoter. In conclusion, MUCs exhibited distinct expression patterns in the gut. Their expression was disrupted in UC, regardless of the treatment protocols. Abnormal MUC1, MUC4, and MUC5B expression marked the barrier dysfunction in UC.

Bioinspired Oligo-Urethane Nanoparticles for Delivering Exogenous C-Type Natriuretic Peptide: Synthetic Biomaterial Nanocarrier Complexes and Their Interactions with Cardiac Myofibroblasts.

In a healthy heart, cells naturally secrete C-type natriuretic peptide (CNP), a cytokine that protects against myofibroblast differentiation of cardiac fibroblasts and extracellular matrix deposition leading to fibrosis. CNP availability during myocardial remodeling is important to prevent cardiac fibrosis, but CNP is limited after an injury because of the loss of cardiomyocytes and the activation of cardiac fibroblasts to myofibroblasts. We hypothesized that the sustained release of exogenous CNP from oligo-urethane nanoparticles (NPs) would reduce differentiation of human cardiac fibroblasts toward a myofibrogenic phenotype. Our work used a modified form of a degradable polar hydrophobic ionic (D-PHI) oligo-urethane, which has shown the ability to self-assemble into NPs for the delivery of peptide and oligonucleotide biomolecules. The CNP-loaded NPs (NPCNP) were characterized for a diameter of 129 ± 1.4 nm and a ζ potential of -46 ± 7.8 mV. Treatment of cardiac fibroblasts with NPCNP increased cyclic guanosine-monophosphate (cGMP) synthesis, confirming that exogenous CNP delivered via oligo-urethane NPs is bioactive and can induce downstream signaling that has been implicated in antagonizing transforming growth factor-ß1 (TGF-ß1)-induced myofibrogenic differentiation. It is also shown that treatment with NPCNP attenuated contraction of collagen gels by cardiac myofibroblasts stimulated with TGF-ß1. Coating with heparin on the NPCNP (HEP-NPCNP) exemplified an approach to extend the release of CNP from the NPs. Both HEP-NPCNP and NPCNP show minimal cell toxicity, studied up to 0.25 × 1010 NPs/mL in culture media. These findings support further investigation of CNP delivery via NPs as a future therapy for suppressing cardiac fibrosis.

Italian Real-Life Experience on the Use of Mogamulizumab in Patients with Cutaneous T-Cell Lymphomas.

Mycosis fungoides and Sèzary syndrome are the most studied subtypes common cutaneous T-cell lymphomas. The current treatment objective is to improve the clinical manifestations of the disease in the affected areas, to relieve symptoms and to halt disease progression. Patients with early-stage mycosis fungoides are usually managed with skin-directed therapies, whereas patients with resistant or advanced-stage mycosis fungoides or Sèzary syndrome often require systemic drugs. Over the last decade, new drugs have been developed, increasing the breadth of treatment options for cutaneous T-cell lymphomas patients. Mogamulizumab is a first-in-class defucosylated humanized IgG1 κ monoclonal antibody, which exerts its anti-tumour action by selectively binding to C-C chemokine receptor 4 and increasing antibody-dependent cellular cytotoxicity activity against malignant T-cells. Several clinical trials showed that mogamulizumab is able to effectively control the cutaneous T-cell lymphomas in each site (skin, blood, lymph nodes and viscera), improving patients' symptoms, function and overall quality of life with a manageable safety profile. In this report, we discuss 12 cases of patients with mycosis fungoides or Sèzary syndrome successfully treated with mogamulizumab in real-life clinical practice in Italy.

The novel role of glucocorticoid-induced leucine zipper as a marker of mucosal healing in inflammatory bowel diseases.

Glucocorticoid-induced leucin zipper (GILZ) mediates the effects of glucocorticoids in immune cells, but little is known about its role in both the gastro-intestinal (GI) mucosa and inflammatory bowel diseases (IBD) in humans. To investigate the GILZ protein expression profile in the GI tract, mucosal biopsies from 80 patients were retrospectively enrolled in this study and subdivided into three groups: 1) patients without clinical-endoscopic and histological evidence of IBD; 2) IBD patients; 3) patients with chronic atrophic gastritis (CAG) and Barrett esophagus (BE), both characterized by intestinal metaplasia (IM). GILZ expression was assessed by immunohistochemical and immunofluorescence methods. Our results showed that GILZ protein was strongly expressed in the secretory cells in healthy mucosa. GILZ expression was reduced in goblet cells in active disease, whereas it was restored in quiescent diseases. Conversely, entero-endocrine cells were not involved in such inflammation-driven dynamics, as GILZ expression remained detectable in active disease. Moreover, GILZ was expressed in IM, but was limited to CAG, and was not detected in BE. In summary, GILZ acts as a secretory protein in the GI mucosa in healthy, hyperplastic and metaplastic conditions. Its secretion by goblet cells is mostly affected by neutrophils mucosal infiltration and seems to be directly related to active mucosal inflammation in IBD. Overall, our findings suggest that GILZ is a suitable molecule to be considered as a histological marker of mucosal healing.

An SCPPPQ1/LAM332 protein complex enhances the adhesion and migration of oral epithelial cells: Implications for dentogingival regeneration.

Common periodontal disease treatment procedures often fail to restore the structural integrity of the junctional epithelium (JE), the epithelial attachment of the gum to the tooth, leaving the tooth-gum interface prone to bacterial colonization. To address this issue, we introduced a novel bio-inspired protein complex comprised of a proline-rich enamel protein, SCPPPQ1, and laminin 332 (LAM332) to enhance the JE attachment. Using quartz crystal microbalance with dissipation monitoring (QCM-D), we showed that SCPPPQ1 and LAM332 interacted and assembled into a protein complex with high-affinity adsorption of 5.9e-8 [M] for hydroxyapatite (HA), the main component of the mineralized tooth surfaces. We then designed a unique shear device to study the adhesion strength of the oral epithelial cells to HA. The SCPPPQ1/LAM332 complex resulted in a twofold enhancement in adhesion strength of the cells to HA compared to LAM332 (from 31 dyn/cm2 to 63 dyn/cm2). In addition, using a modified wound-healing assay, we showed that gingival epithelial cells demonstrated a significantly high migration rate of 2.7 ± 0.24 µm/min over SCPPPQ1/LAM332-coated surfaces. Our collective data show that this protein complex has the potential to be further developed in designing a bioadhesive to enhance the JE attachment and protect the underlying connective tissue from bacterial invasion. However, its efficacy for wound healing requires further testing in vivo. STATEMENT OF SIGNIFICANCE: This work is the first functional study towards understanding the combined role of the enamel protein SCPPPQ1 and laminin 332 (LAM332) in the epithelial attachment of the gum, the junctional epithelium (JE), to the tooth hydroxyapatite surfaces. Such studies are essential for developing therapeutic approaches to restore the integrity of the JE in the destructive form of gum infection. We have developed a model system that provided the first evidence of the strong interaction between SCPPPQ1 and LAM332 on hydroxyapatite surfaces that favored protein adsorption and subsequently oral epithelial cell attachment and migration. Our collective data strongly suggested using the SCPPPQ1/LAM332 complex to accelerate the reestablishment of the JE after surgical gum removal to facilitate gum regeneration.

Discoidin domain receptor 1-deletion ameliorates fibrosis and promotes adipose tissue beiging, brown fat activity, and increased metabolic rate in a mouse model of cardiometabolic disease.

OBJECTIVE: Discoidin domain receptor 1 (DDR1) is a collagen binding receptor tyrosine kinase implicated in atherosclerosis, fibrosis, and cancer. Our previous research showed that DDR1 could regulate smooth muscle cell trans-differentiation, fibrosis and calcification in the vascular system in cardiometabolic disease. This spectrum of activity led us to question whether DDR1 might also regulate adipose tissue fibrosis and remodeling. METHODS: We have used a diet-induced mouse model of cardiometabolic disease to determine whether DDR1 deletion impacts upon adipose tissue remodeling and metabolic dysfunction. Mice were fed a high fat diet (HFD) for 12 weeks, followed by assessment of glucose and insulin tolerance, respiration via indirect calorimetry, and brown fat activity by FDG-PET. RESULTS: Feeding HFD induced DDR1 expression in white adipose tissue, which correlated with adipose tissue expansion and fibrosis. Ddr1-/- mice fed an HFD had improved glucose tolerance, reduced body fat, and increased brown fat activity and energy expenditure compared to Ddr1+/+ littermate controls. HFD-fed DDR1-/- mice also had reduced fibrosis, smaller adipocytes with multilocular lipid droplets, and increased UCP-1 expression characteristic of beige fat formation in subcutaneous adipose tissue. In vitro, studying C3H10T1/2 cells stimulated to differentiate, DDR1 inhibition caused a shift from white to beige adipocyte differentiation, whereas DDR1 expression was increased with TGFß-mediated pro-fibrotic differentiation. CONCLUSION: This study is the first to identify a role for DDR1 as a driver of adipose tissue fibrosis and suppressor of beneficial beige fat formation.

Deficiency of Natriuretic Peptide Receptor 2 Promotes Bicuspid Aortic Valves, Aortic Valve Disease, Left Ventricular Dysfunction, and Ascending Aortic Dilatations in Mice.

RATIONALE: Aortic valve disease is a cell-mediated process without effective pharmacotherapy. CNP (C-type natriuretic peptide) inhibits myofibrogenesis and osteogenesis of cultured valve interstitial cells and is downregulated in stenotic aortic valves. However, it is unknown whether CNP signaling regulates aortic valve health in vivo. OBJECTIVE: The aim of this study is to determine whether a deficient CNP signaling axis in mice causes accelerated progression of aortic valve disease. METHODS AND RESULTS: In cultured porcine valve interstitial cells, CNP inhibited pathological differentiation via the guanylate cyclase NPR2 (natriuretic peptide receptor 2) and not the G-protein-coupled clearance receptor NPR3 (natriuretic peptide receptor 3). We used Npr2+/- and Npr2+/-;Ldlr-/- mice and wild-type littermate controls to examine the valvular effects of deficient CNP/NPR2 signaling in vivo, in the context of both moderate and advanced aortic valve disease. Myofibrogenesis in cultured Npr2+/- fibroblasts was insensitive to CNP treatment, whereas aged Npr2+/- and Npr2+/-;Ldlr-/- mice developed cardiac dysfunction and ventricular fibrosis. Aortic valve function was significantly impaired in Npr2+/- and Npr2+/-;Ldlr-/- mice versus wild-type littermates, with increased valve thickening, myofibrogenesis, osteogenesis, proteoglycan synthesis, collagen accumulation, and calcification. 9.4% of mice heterozygous for Npr2 had congenital bicuspid aortic valves, with worse aortic valve function, fibrosis, and calcification than those Npr2+/- with typical tricuspid aortic valves or all wild-type littermate controls. Moreover, cGK (cGMP-dependent protein kinase) activity was downregulated in Npr2+/- valves, and CNP triggered synthesis of cGMP and activation of cGK1 (cGMP-dependent protein kinase 1) in cultured porcine valve interstitial cells. Finally, aged Npr2+/-;Ldlr-/- mice developed dilatation of the ascending aortic, with greater aneurysmal progression in Npr2+/- mice with bicuspid aortic valves than those with tricuspid valves. CONCLUSIONS: Our data establish CNP/NPR2 signaling as a novel regulator of aortic valve development and disease and elucidate the therapeutic potential of targeting this pathway to arrest disease progression.

Impacto de la vacuna neumocócica conjugada 13-valente en la incidencia de neumonía consolidante en menores de 5 anos en el partido de Pilar, Buenos Aires: estudio de base poblacional / Impact of the 13-valent pneumococcal conjugate vaccine on the incidence of consolidated pneumonia in children younger than 5 years old in Pilar, Buenos Aires: A population-based study

Introducción. En enero de 2012, en Argentina, fue introducida la vacuna neumocócica conjugada 13-valente (13-Valent Pneumococcal Conjugate Vaccine; PCV13, por sus siglas en inglés) en el Calendario Nacional, en menores de 2 anos. La cobertura en el partido de Pilar en 2012 fue > 90% para las primeras 2 dosis y 60% para la tercera. Objetivo. Medir la efectividad de la PCV13 en la reducción de la incidencia de neumonías consolidantes (NC), durante los dos anos siguientes a su introducción en el Calendario. Métodos. Estudio prospectivo debase poblacional en Pilar. Se incluyeron todos los menores de 5 anos con signos clínicos de neumonía atendidos en hospitales de referencia (ambulatorios y hospitalizados) en los primeros 2 anos de la incorporación (2012-2013). Se comparó la incidencia anual de NC con el período basal 2003-2005. Evaluación clínica-radiológica, según criterio de la Organización Mundial de la Salud. Resultados. Se incluyeron 666 pacientes con sospecha clínica de neumonía. Se diagnosticó NC en 309 pacientes; 52,1% de mujeres, 70,2% menores de 2 anos y 56,4% vacunado con PCV13; 4,5% (14/309) con bacteriología confirmada (S. pneumoniae: 4; N. meningitidis: 4; S. aureus: 2; otros: 4). Se observó una reducción significativa en la incidencia de NC (por 100000 niños menores de 5 anos) entre los períodos pre y posvacunal de 750 (204/27209) a 561 (171/30 475) en 2012 y 453 (138/30 475) en 2013; efectividad de 25,2% y 39,6%, respectivamente. Reducción en menores de 1 año: 33,9% en 2012 y 44,6% en 2013; y en niños de 12-23 meses: 57,9% en 2013. No se observaron diferencias significativas en las incidencias en edades mayores. Conclusiones. Luego de la introducción de la PCV13 en el Calendario de Vacunación en Argentina, se observó una reducción rápida y significativa en la incidencia de NC, principalmente en menores de 1 año en 2012 y menores de 2 anos en 2013.

Introduction. In January 2012, Argentina introduced the 13-valent pneumococcal conjugate vaccine (PCV13) in its immunization schedule for children younger than 2 years old. Coverage in Pilar in 2012 reached>90% for the first two doses and 60% for the third dose. Objective. To measure the effectiveness of PCV13 to reduce the incidence of consolidated pneumonia (CP)in the two-year period following its introduction in the immunization schedule. Methods. Prospective, population-based study conducted in Pilar. All children younger than 5 year sold with clinical signs of pneumonia assisted at the reference hospitals (both inpatients and utpatients) in the first two years since the vaccine introduction (2012-2013) were included. The annual incidence of CP was compared to the 2003-2005 baseline period. Clinical and radiological assessments were done as per the World Health Organization's criteria. Results. Six hundred and sixty-six patients with clinical suspicion of pneumonia were included. CP was diagnosed in 309 patients; 52.1% were girls, 70.2% were younger than 2 years old, and 56.4% had been immunized with the PCV13; 4.5% (14/309) had bacteriological confirmation (S. pneumoniae: 4; N. meningitidis: 4; S. aureus: 2; others: 4). A significant reduction in the incidence of CP (per 100 000 children younger than 5 years old) was observed between the pre- and postimmunization periods, from 750 (204/27209) to 561 (171/30 475) in 2012 and to 453 (138/30 475) in 2013; effectiveness accounted for 25.2% and 39.6%, respectively. Reduction in infants younger than 1 year old: 33.9% in 2012 and 44.6% in 2013; and in children aged 12-23 months old: 57.9% in 2013. No significant differences were observed in the incidence of CP at an older age. Conclusions. Following the introduction of PCV13 in Argentina's immunization schedule, a fast and significant reduction in the incidence of CP was observed, mainly in infants younger than 1 year old in 2012 and in children younger than 2 years old in 2013.

[Impact of the 13-valent pneumococcal conjugate vaccine on the incidence of consolidated pneumonia in children younger than 5 years old in Pilar, Buenos Aires: A population-based study]. / Impacto de la vacuna neumocócica conjugada 13-valente en la incidencia de neumonía consolidante en menores de 5 anos en el partido de Pilar, Buenos Aires: estudio de base poblacional.

INTRODUCTION: In January 2012, Argentina introduced the 13-valent pneumococcal conjugate vaccine (PCV13) in its immunization schedule for children younger than 2 years old. Coverage in Pilar in 2012 reached>90% for the first two doses and 60% for the third dose. OBJECTIVE: To measure the effectiveness of PCV13 to reduce the incidence of consolidated pneumonia (CP)in the two-year period following its introduction in the immunization schedule. METHODS: Prospective, population-based study conducted in Pilar. All children younger than 5 year sold with clinical signs of pneumonia assisted at the reference hospitals (both inpatients and outpatients) in the first two years since the vaccine introduction (2012-2013) were included. The annual incidence of CP was compared to the 2003-2005 baseline period. Clinical and radiological assessments were done as per the World Health Organization's criteria. RESULTS: Six hundred and sixty-six patients with clinical suspicion of pneumonia were included. CP was diagnosed in 309 patients; 52.1% were girls, 70.2% were younger than 2 years old, and 56.4% had been immunized with the PCV13; 4.5% (14/309) had bacteriological confirmation (S. pneumoniae: 4; N. meningitidis: 4; S. aureus: 2; others: 4). A significant reduction in the incidence of CP (per 100 000 children younger than 5 years old) was observed between the pre- and postimmunization periods, from 750 (204/27209) to 561 (171/30 475) in 2012 and to 453 (138/30 475) in 2013; effectiveness accounted for 25.2% and 39.6%, respectively. Reduction in infants younger than 1 year old: 33.9% in 2012 and 44.6% in 2013; and in children aged 12-23 months old: 57.9% in 2013. No significant differences were observed in the incidence of CP at an older age. CONCLUSIONS: Following the introduction of PCV13 in Argentina's immunization schedule, a fast and significant reduction in the incidence of CP was observed, mainly in infants younger than 1 year old in 2012 and in children younger than 2 years old in 2013.

Introducción. En enero de 2012, en Argentina, fue introducida la vacuna neumocócica conjugada 13-valente (13-Valent Pneumococcal Conjugate Vaccine; PCV13, por sus siglas en inglés) en el Calendario Nacional, en menores de 2 años. La cobertura en el partido de Pilar en 2012 fue > 90% para las primeras 2 dosis y 60% para la tercera. Objetivo. Medir la efectividad de la PCV13 en la reducción de la incidencia de neumonías consolidantes (NC), durante los dos años siguientes a su introducción en el Calendario. Métodos. Estudio prospectivo de base poblacional en Pilar. Se incluyeron todos los menores de 5 años con signos clínicos de neumonía atendidos en hospitales de referencia (ambulatorios y hospitalizados) en los primeros 2 años de la incorporación (2012-2013). Se comparó la incidencia anual de NC con el período basal 2003-2005. Evaluación clínica-radiológica, según criterio de la Organización Mundial de la Salud. Resultados. Se incluyeron 666 pacientes con sospecha clínica de neumonía. Se diagnosticó NC en 309 pacientes; 52,1% de mujeres, 70,2% menores de 2 años y 56,4% vacunado con PCV13; 4,5% (14/309) con bacteriología confirmada (S. pneumoniae: 4; N. meningitidis: 4; S. aureus: 2; otros: 4). Se observó una reducción significativa en la incidencia de NC (por 100 000 niños menores de 5 años) entre los períodos pre y posvacunal de 750 (204/27 209) a 561 (171/30 475) en 2012 y 453 (138/30 475) en 2013; efectividad de 25,2% y 39,6%, respectivamente. Reducción en menores de 1 año: 33,9% en 2012 y 44,6% en 2013; y en niños de 12-23 meses: 57,9% en 2013. No se observaron diferencias significativas en las incidencias en edades mayores. Conclusiones. Luego de la introducción de la PCV13 en el Calendario de Vacunación en Argentina, se observó una reducción rápida y significativa en la incidencia de NC, principalmente en menores de 1 año en 2012 y menores de 2 años en 2013.

The coxsackie-adenovirus receptor induces an inflammatory cardiomyopathy independent of viral infection.

The coxsackie-adenovirus receptor (CAR) is a viral receptor for Group B coxsackieviruses (CVBs) and adenoviruses. CAR has been linked with the innate immune response to CVB myocarditis, and with activation of inflammatory cells in vitro. We hypothesized that CAR activates signals that promote inflammation in the myocardium independent of viral infection. To test this we conditionally overexpressed murine CAR in cardiomyocytes of adult binary transgenic mice under the control of a tetracycline-responsive (tet-off) α-myosin heavy chain (αMtTA) promoter (mCAR(+)/αMtTA(+) mice). An inflammatory cardiomyopathy developed in both lines generated (6-mCAR(+)/αMtTA(+) and 12-mCAR(+)/αMtTA(+)) following withdrawal of doxycycline. Cardiac CAR was upregulated at 4weeks of age in 6-mCAR(+)/αMtTA(+) mice and induced a mild inflammatory infiltrate (score 1.3 of 4.0±0.3) at 6weeks, with 95% of mice surviving to that time. In the second line, 12-mCAR(+)/αMtTA(+) mice, CAR was upregulated in the majority of mice by 3weeks of age, and by 5weeks of age more severe cardiac inflammation (score 2.8 of 4.0±0.4) developed with only 56% of mice surviving. The cardiac inflammatory infiltrate was primarily natural killer cells and macrophages in both mCAR(+)/αMtTA(+) lines. A proinflammatory cytokine response with increased cardiac interferon-γ, interleukin (IL)-12, IL-1ß, tumor necrosis factor-α and IL-6 was detected by real-time RT-PCR. CAR has been linked to signaling via the inflammatory mitogen-activated protein kinase (MAPK) cascades; therefore, we evaluated the response of these pathways in hearts with upregulated CAR. Both stress-activated JNK and p38MAPK were activated in mCAR(+)/αMtTA(+) hearts prior to onset of inflammation and in isolated mCAR(+)/αMtTA(+) cardiomyocytes. In conclusion, we show for the first time that CAR upregulation in the adult mouse heart induces cardiac inflammation reminiscent of early viral myocarditis. CAR-induced stress-activated MAPK signaling may contribute to the development of cardiac inflammation unrelated to viral infection per se.

Cardiomyocyte-targeted overexpression of the coxsackie-adenovirus receptor causes a cardiomyopathy in association with beta-catenin signaling.

The coxsackie-adenovirus receptor (CAR) is an adhesion molecule found at the intercalated disc of cardiomyocytes in association with other adherens and tight junction proteins. CAR expression is increased at cardiomyocyte junctions in patients with heart failure. It is not known what contribution elevated CAR expression makes to cardiac pathology. We generated a binary transgenic mouse enabling cardiac-restricted doxycycline-regulated expression of Flag-tagged murine CAR (mCAR(+)/alpha MtTA(+) mice). Myocardial CAR levels were increased 6-fold in mCAR(+)/alpha MtTA(+) mice, localizing to intercalated discs and sarcolemma. Well at birth, mCAR(+)/alpha MtTA(+) mice developed a severe cardiomyopathy and died by 4 weeks. Cardiomyocyte hypertrophy was evident at 1 week, with increased heart:body weight ratios by 3 weeks. Disorganization and degeneration of cardiomyocytes were evident with disrupted adherens junctions. Doxycycline administration turned off transgene expression and rescued mice from the development of the cardiomyopathic phenotype. In CAR-overexpressing mCAR(+)/alpha MtTA(+) mice, adherens junction proteins were abnormally expressed. N-cadherin protein levels were 83% lower in mCAR(+)/alpha MtTA(+) hearts vs controls at 1 week, with levels subsequently increased above controls at 3 weeks. beta-catenin expression was 90% and 135% above controls at 1 and 3 weeks, respectively. Nuclear translocation of beta-catenin in cardiomyocytes of mCAR(+)/alpha MtTA(+) mice was associated with increased c-myc RNA, a target of active beta-catenin known to be associated with cardiac hypertrophy. Our study is the first to demonstrate that increased CAR expression can induce a cardiomyopathy and supports a model whereby the pathogenesis is determined by CAR stimulated beta-catenin signaling, and/or disruption of the adherens junction.

Necrotizing fasciitis. Case report.

Necrotizing fasciitis (NF) is an infection localized at the fascial structures (both the superficial and deep ones) layering the muscles though never affecting them. NF death rate is very high (20-40%). NF can be a post-surgery, traumatic or infective complication and its prognosis quoad vitam is fatal without a timely and correct therapy. A 57-year-old woman was got into observation due to her temperature, left thigh pain, erythema and tumefaction in the left groin-crural seat. She suffered from obesity, insulin-dependent mellitus diabetes and modest but chronic renal failure and ischaemic cardiopathy from previous Acute Myocardial Infarctions. It was then started a wide-spectrum antibiotics therapy. But after just six hours there took place a rapid development of the clinical picture with the appearance of haemorrhagic-content blisters and areas of cutaneous necrosis. The patient therefore underwent-under general anaestesia-multiple incisions in the groin-crural seat and on the ipsilateral thigh. The multiple biopsies carried out during the operation too underwent cultural and histomorphopathological analysis. The anatomic pathological study highlighted the presence of necrosis of the fascia, vascular thrombosis and myonecrosis. The cultural analysis of the tissue biopsies showed a polymicrobial infection. Both the pharmacological therapy and the surgical cleaning were carried out daily but without any improvement of the clinical picture. On the eighth day a worsening of the patient's general conditions took place, with a multiple organ failure determining the patient's exitus.

Antitumor activity of bortezomib alone and in combination with TRAIL in human acute myeloid leukemia.

Acute myeloid leukemia (AML) is a malignant disease characterized by abnormal proliferation of clonal precursor cells. Although different strategies have been adopted to obtain complete remission, the disease actually progresses in about 60-70% of patients. Bortezomib has been used in multiple myeloma and other lymphoid malignancies because of its antitumor activity. Here we examined the sensitivity of bone marrow cells from AML patients (34 patients: 25 newly diagnosed, 4 relapsed, 5 refractory) to bortezomib alone or in combination with TRAIL, a member of the TNF family that induces apoptosis in tumor cells while sparing normal cells. Bortezomib induced cell death in blasts from each patient sample. The cytotoxic effect was dose- and time-dependent (concentration from 0.001 to 10 microM for 24 and 48 h) and was associated with a downregulation of Bcl-xL and Mcl-1, an upregulation of TRAIL-R1, TRAIL-R2, p21, activation of executioner caspases and a loss of the mitochondrial membrane potential. Moreover, low doses of bortezomib primed TRAIL-resistant AML cells for enhanced TRAIL-mediated killing. These results suggest that a combination of proteasome inhibitors and TRAIL could be effective for treating AML patients, even patients who are refractory to conventional chemotherapy.

[Thyroid diseases in elderly patients]. / Disfunzioni tiroidee in età geriatrica.

AIM OF THE STUDY: To evaluate the differences about incidence, kind and clinical features of thyroid diseases in young and elderly patients. MATERIALS AND METHODS: Our study has been conducted in Endocrine Surgery Unit, "S. Luigi and S. Currò" Hospital in Catania, from January 2001 to December 2003. In this period 621 patients affected with different thyroidopathies were observed. They were divided in two groups: elderly (65 years or older), named Group A, and young subjects (under 65 years old), named Group B. Group A included 147 people aged between 65 and 89, with F:M = 3.9:1. Our study was founded on clinical and laboratory evaluation of thyroid hormones and antibodies (AAT, AMT) and subsequently an ultrasonographical evaluation, that has been completed, in some cases, with cytologic examination (FNAc). CONCLUSION: The main aspect about thyroid diseases is the different and atypical presentation in the elderly in comparison to young patients, with subsequent difficult diagnosis due to common symptoms to thyroidopathies rather than to physiological ageing. The most common thyroid dysfunctions in elderly are the autoimmune thyroidopathies, responsible of hypothyroidism. Such condition, in elderly, is often clinically irrelevant.

[Hashimoto thyroiditis. Possible cause or consequence of a malignant thyroid tumor]. / Tiroidite di Hashimoto: possibile causa o conseguenza del tumore tiroideo maligno.

AIM OF THE STUDY: The Authors performed a retrospective study on their case records in order to analyze the epidemiological aspects of association between Hashimoto thyroiditis and differentiated thyroid carcinoma. MATERIALS AND METHODS: From January 2004 to December 2005 the Authors performed 282 total thyroidectomy for any thyroid pathology. All patients were studied preoperatively even dosing antithyroid antibodies. In the study are included patients who presented histological finding of both Hashimoto thyroiditis and carcinoma. RESULTS: Eleven patients (23.9%) of 46 patients operated on for differentiated thyroid carcinoma also presented histological finding of thyroiditis. Association of thyroiditis and carcinoma was present in 39.2% of histologically detecied thyroiditis (28 patiems). CONCLUSIONS: Pathophysiological relationship between Hashimoto thyroiditis and DTC are still unclear, although a certain association of theese two anatomo-clinic entity has been demonstrated. We can't yet say if Hashimoto thyroiditis advance and facilitale tumour arising or thyroiditis is a reaction to neoplasia or these two pathologies are indipendeni each other, although both are present in the same patient.

[Thyroid microcarcinoma in benign thyroid diseases]. / Il microcarcinoma tiroideo nelle tireopatie benigne.

INTRODUCTION: Thyroid microcarcinoma is a malignant thyroid tumor with potential multifocality and a maximum of 1 cm of diameter. This carcinoma has been discovered more frequently like incidentaloma. AIM OF THE STUDY: To appraise the incidence of MCT in the benign thyroid diseases and the advantages offered from the total thyroidectomy, performed for benign diffused thyroid diseases, which surgical treatment "therapeutic" performed for these malignant tumors. MATERIALS AND METHODS: The study was conducted on 600 patients operated with total thyroidectomy for benign thyroid disease, admitted from 1999 to 2003. RESULTS: All patients were alive and free of disease at last control. DISCUSSION: The MCT is a carcinoma that presents frequently a behavior little malignant and a good prognosis. His principal characteristic is the absence of clinical demonstrations. Therefore his discovery, almost always accidental on a thyroid removed for other pathology, it has signaled by histologic study CONCLUSIONS: Thyroid microcarcinoma is a slow growing tumor, with a good prognosis and with a good disease-free survival. It can present a better aggressiveness for his multifocal localization and invasion. Therefore total thyroidectomy can be considered best treatment and also be surgical treatment oncologically correct for this tumor.

[The lobe of Zuckerkandl: an important sign of recurrent laryngeal nerve]. / Il lobo di Zuckerkandl: faro del nervo laringeo ricorrente.

INTRODUCTION: The accurate acquaintance of the anatomy of the thyroid gland allows reduction of complications to interventions of thyroidectomy, where for the existing topography, the nervous and vascular structures could result vulnerable. The identification of Zuckerkandl's tuberculum could reduce the lesions to the recurrent laryngeal nerve, for constant relationship between the recurrent laryngeal nerve and tuberculum. MATERIALS AND METHODS: The Authors have studied 605 patients underwent to thyroid surgery for benign or malignant thyroid diseases. The aim was to verify if the incidence of recurrent nerve lesions can be reduced with the identification of the Zuckerkandl's tuberculum and with a knowledge of its anatomical relationships with vascular, nervous and glandular structures near the thyroid. RESULTS: The Zuckerkandls tuberculum was found in the majority of the cases, with prevalence to the right. Its identification has allowed an immediate and safe identification of recurrent laryngeal nerve, with setting of time of the operation and especially with setting of possible injury to the recurrent nerves. DISCUSSION: The lobe of Zuckerkandl is the extension of the lateral lobes of the thyroid, composed of thyroid tissue only and so it can be interested in thyroid lesions. This tubercle is considered a constant anatomical landmark for the recurrent laryngeal nerve and the superior parathyroid glands. The knowledge of the lobe of Zuckerkandl is essential to perform "safety thyroidectomy", without injury for the vascular and nervous structures. CONCLUSIONS: TZ identification is not always easy and/or possible but, when that happens become aware of possible, systematically, the isolation of the recurrent nerve and of the superior parathyroid gland, preserve such structures from possible lesions in surgery of the thyroid gland.