Profiles of sulfonylurea use in Diabetes Mellitus type 2: An analysis of clinical practice over the last 10 years.

AIMS: Describing the evolution over time in the use of sulfonylureas (SUs) and the characteristics of patients at first prescription and at interruption of treatment with SUs. METHODS: Retrospective evaluation of data from the Italian Association of Diabetologists (AMD) Annals registry (2010-2020), about T2D patients who started treatment with SUs. The longitudinal probability of remaining on SUs was estimated by Kaplan Meier survival curves. RESULTS: SU prescription decreased from 30.7 % (2010) to 12.9 % (2020). Patients started on SU were 68.2 ±â€¯11.2 years old, mostly males (55.5 %), with diabetes duration = 10.1 ±â€¯8.3 years, BMI = 29.7 ±â€¯5.5 kg/m2, and HbA1c = 8.3 ±â€¯1.7 % [67 mmol/mol]. After one year, the probability of staying on SU was 85.4 %, 75.9 % after two years, 68.2 % after 3 years, 56.6 % after 5 years. Patients who discontinued SUs had higher BMI and HbA1c, were younger, more often males and treated with insulin. Over time, the percentage of subjects switched to metformin, DPP4i, SGLT2i, and GLP1RA increased, whereas use of glinides, glitazones, acarbose and insulin declined. CONCLUSIONS: These data suggest a consensus, slowly, but increasingly aligning with the current National indications of dismissing SUs for the treatment of T2D. The new drugs for diabetes should represent a preferable choice in all patients who do not have specific contraindications.

Subclinical hypothyroidism in children: is it always subclinical?

Aim of this commentary is to report current knowledges on the main clinical and metabolic abnormalities which might be observed in children with longstanding and untreated subclinical hypothyroidism (SH) and to comment the most recent views about natural evolution of thyroid function in the cases with either idiopathic or Hashimoto's thyroiditis-related SH. On the basis of these preliminary remarks, the essential guidelines for an appropriate and tailored management of SH children are also proposed.

Neuronal cell adhesion genes and antidepressant response in three independent samples.

Drug-effect phenotypes in human lymphoblastoid cell lines recently allowed to identify CHL1 (cell adhesion molecule with homology to L1CAM), GAP43 (growth-associated protein 43) and ITGB3 (integrin beta 3) as new candidates for involvement in the antidepressant effect. CHL1 and ITGB3 code for adhesion molecules, while GAP43 codes for a neuron-specific cytosolic protein expressed in neuronal growth cones; all the three gene products are involved in synaptic plasticity. Sixteen polymorphisms in these genes were genotyped in two samples (n=369 and 90) with diagnosis of major depressive episode who were treated with antidepressants in a naturalistic setting. Phenotypes were response, remission and treatment-resistant depression. Logistic regression including appropriate covariates was performed. Genes associated with outcomes were investigated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) genome-wide study (n=1861) as both individual genes and through a pathway analysis (Reactome and String databases). Gene-based analysis suggested CHL1 rs4003413, GAP43 rs283393 and rs9860828, ITGB3 rs3809865 as the top candidates due to their replication across the largest original sample and the STAR*D cohort. GAP43 molecular pathway was associated with both response and remission in the STAR*D, with ELAVL4 representing the gene with the highest percentage of single nucleotide polymorphisms (SNPs) associated with outcomes. Other promising genes emerging from the pathway analysis were ITGB1 and NRP1. The present study was the first to analyze cell adhesion genes and their molecular pathways in antidepressant response. Genes and biomarkers involved in neuronal adhesion should be considered by further studies aimed to identify predictors of antidepressant response.

PPP3CC gene: a putative modulator of antidepressant response through the B-cell receptor signaling pathway.

Antidepressant pharmacogenetics represents a stimulating, but often discouraging field. The present study proposes a combination of several methodologies across three independent samples. Genes belonging to monoamine, neuroplasticity, circadian rhythm and transcription factor pathways were investigated in two samples (n=369 and 88) with diagnosis of major depression who were treated with antidepressants. Phenotypes were response, remission and treatment-resistant depression. Logistic regression including appropriate covariates was performed. Genes associated with outcomes were investigated in the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) genome-wide study (n=1861). Top genes were further studied through a pathway analysis. In both original samples, markers associated with outcomes were concentrated in the PPP3CC gene. Other interesting findings were particularly in the HTR2A gene in one original sample and the STAR*D. The B-cell receptor signaling pathway proved to be the putative mediator of PPP3CC's effect on antidepressant response (P=0.03). Among innovative candidates, PPP3CC, involved in the regulation of immune system and synaptic plasticity, seems promising for further investigation.

Isolated fracture of the capitate with rotation of the proximal fragment. Case report.

A case of capitate fracture in a 28-year-old man, with a 180-degree rotation (volar dislocation) of the proximal fragment is reported. Due to a late diagnosis, the patient presented 2 weeks after trauma. Open reduction and internal fixation with Kirschner wires provided good bone alignment, uneventful healing and a good range of wrist motion was achieved. The authors remind the reader the possibility of capitate fracture, a rare but troublesome event among wrist traumas, requiring a prompt diagnosis and treatment to relief important wrist pain and to restore function. Moreover, in consideration of important vascular complications, producing non-union and arthritis, the emerging role of imaging in detecting even minor signs of bone necrosis, leading to correct surgical indications, has to be taken into account.

Neutrophil-rich gastric carcinomas: light and electron microscopic study of 9 cases with particular reference to neutrophil apoptosis.

The authors report 9 cases of gastric carcinomas characterized by a prominent neutrophilic infiltration of the stroma. These tumors (8 of intestinal type, 1 of diffuse type) showed a pushing growth pattern. Metastatic involvement of regional lymph nodes was seen in 5 cases. The metastatic foci were associated with heavy neutrophilia as well. There was no histologic evidence of Helicobacter pylori infection, whereas various degrees of multifocal intestinal metaplasia were present in the background mucosa. Based on histologic and histochemical results, there were no apparent causes due to other infectious agents responsible for the neutrophil-rich gastric carcinomas. Some of intraepithelial and stromal neutrophils exhibited apoptotic changes, such as chromatin condensation and cell shrinkage, and were TUNEL-positive. Electron microscopy disclosed apoptotic neutrophils in cytoplasmic vacuoles of tumor cells, a finding suggestive of neutrophil-tumor cell phagocytosis (cannibalism). Different stages of neutrophil apoptosis were also shown by electron microscopy and the ultrastructural findings were compared to those described in experimental models, both in vivo and in vitro.

A genetic dissection of antipsychotic induced movement disorders.

BACKGROUND: Antipsychotic medications (APM) are the first line pharmacological treatment for psychotic disorders and other behavioral disorders. Nevertheless, their use causes a number of side effects, including extrapyramidal symptoms (EPS). EPS decrease the efficacy of the antipsychotic treatments by causing poorer compliance to the treatment, stigma and a poorer quality of life for patients. Genetic studies hold the potential to unravel the molecular underpinnings of the EPS induced by APM but results are not conclusive and are far to be used in clinical practice despite decades of research. A more sophisticated selection of the list of genetic mutations explaining the genetic variance of EPS induced by APM could help in the definition of a personalized treatments for patients. Moreover, it would increase the quality of the current treatments with APM. METHODS: We reviewed the literature searching for the genetic association studies focused on dystonia, parkinsonism, akathisia and tardive dyskinesia. Moreover, we reviewed the current biological knowledge of the APM induced side effects. Finally, we provide a reasoned list of candidate genes and their genetic variations, with the aim of identifying a list of candidates for APM induced EPS genetic investigations. RESULTS: Variations located within PIK3CA (phosphoinositide-3- kinase, catalytic, alpha polypeptide), PLA2G4A (phospholipase A2, group IVA, cytosolic, calcium-dependent), PRKCA (protein kinase C, alpha), PRKACG (Phosphatidylinositol-4,5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma), ERK-1 (extracellular signalregulated kinase 1 (MAPK3)), ERK-2 (extracellular signal-regulated kinase 2 (MAPK1)), GNAS (guanine nucleotide binding protein (G protein), alpha stimulating activity polypeptide 1), PLCB1 (phospholipase C, beta 1 (phosphoinositide-specific)) and ITPR1 (inositol 1,4,5-triphosphate receptor type 1) were found to be relevant for APM induced EPS. Some of the genes are classical candidates for this kind of research, others were never investigated. For each of these genes we provide a list of variations that balances the limitations of multitesting with the advantages of the tagging approach. CONCLUSIONS: We undertook a review of the literature about the APM induced EPM to provide some rational genetic candidates to be tested in further genetic investigations.

Granulomatous inflammatory reaction in human gastric adenocarcinomas: a light and electron microscopy study.

Granuloma is a focal, compact collection of inflammatory cells in which mononuclear phagocytes predominate. The authors report 9 cases of papillary-tubular gastric adenocarcinomas characterized by mature granulomas associated with recent microhemorrhages. Mature granulomas were composed of foamy, CD68-positive histiocytes with occasional giant cells. Hemosiderin-containing macrophages were present in the tumor stroma, suggesting phagocytosis of erythrocytes. Under electron microscopy, mature (nonepithelioid) granulomas and clusters containing 1 macrophage and 1-3 eosinophils were found. This study provides morphological examples of skewed type II macrophage infiltration in gastric adenocarcinomas that is involved in scavenging activity, particularly erythrophagocytosis, formation of mature (nonepithelioid granulomas), and heterotypic aggregation with eosinophils.

Effect of PD98059, a selective MAPK3/MAPK1 inhibitor, on acute lung injury in mice.

The aim of the present study is to evaluate the contribution of mitogen-activated protein kinase 1-3 MAPK3/MAPK1) in a model of acute lung inflammation in mice. Injection of carrageenan into the pleural cavity of mice elicited an acute inflammatory response characterized by: accumulation of fluid containing a large number of neutrophils (PMNs) in the pleural cavity, infiltration of PMNs in lung tissues and subsequent adhesion molecule expression (I-CAM and P-selectin), lipid peroxidation, and increased production of tumour necrosis factor-alpha, (TNF-alpha) and interleukin-1beta (IL-1beta). Furthermore, carrageenan induced lung apoptosis (Bax and Bcl-2 expression) as well as nitrotyrosine formation, NF-kB activation, and pJNK expression, as determined by immunohistochemical analysis of lung tissues and the degree of lung inflammation and tissue injury (histological score). Administration of PD98059, an inhibitor of MAPK3/MAPK1 (10 mg/kg) 1 h after carrageenan caused a reduction in all the parameters of inflammation measured. Thus, based on these findings we propose that inhibitors of the MAPK3/MAPK1 signaling pathways, such as PD98059, may be useful in the treatment of various inflammatory diseases.

Krukenberg tumour of the ovary: a case report with light microscopy, immunohistochemistry and electron microscopy study.

A rare case of a 46-year-old woman with bilateral Krukenberg tumours is reported. Histologically, oedematous ovarian stroma was infiltrated by signet-ring cells arranged singly, in cords or in nests. Immunoreactivity for cytokeratin-7, carcinoembryonic antigen as well as histochemical positivity for mucins demonstrated the epithelial nature of the tumour. The gastric primary site was suggested by the cytoplasmic immunoreactivity for MUC-5AC and by ultrastructural evidence of gastric differentiation in signet-ring cells such as mucous granules with eccentric dense cores and intracellular microcysts, lined by sparse microvilli. Gastric biopsy, performed after pathological diagnosis, revealed a signet-ring cell carcinoma similar to that in the ovaries, confirming the gastric origin of the Krukenberg tumour. Because none of the individual immunohistochemical markers used for tissue identification is both site specific and site sensitive, electron microscopy in combination with immunohistochemistry is a valuable tool for the pathologist in the diagnosis of the tissue origin of a Krukenberg tumour.

Effect of tumour necrosis factor-alpha receptor 1 genetic deletion on carrageenan-induced acute inflammation: a comparison with etanercept.

In the present study, we used tumour necrosis factor-alpha receptor 1 knock-out mice (TNF-alphaR1KO) to evaluate an in vivo role of TNF-alphaR1 on the pathogenesis of inflammatory diseases. We used a murine model of carrageenan-induced acute inflammation (pleurisy), a preclinical model of airway inflammation. The data proved that TNF-alphaR1KO were resistant to carrageenan-induced acute inflammation compared with TNF-alpha wild-type mice. TNF-alphaR1KO showed a significant reduction in accumulation of pleural exudate and in the number of inflammatory cells, in lung infiltration of polymorphonuclear leucocytes and lipid peroxidation and showed a decreased production of nitrite/nitrate in pleural exudates. Furthermore, the intensity and degree of the adhesion molecule intercellular adhesion molecule-1 and P-selectin, Fas ligand (FasL), inducible nitric oxide sythase and nitrotyrosine determined by immunohistochemical analysis were reduced markedly in lung tissues from TNF-alphaR1KO at 4 h and 24 h after carrageenan injection. Moreover, TNF-alpha and interleukin-1beta concentrations were reduced in inflamed areas and in pleural exudates from TNF-alphaR1KO. To support the results generated using pleural inflammation, carrageenan-induced paw oedema models were also performed. In order to elucidate whether the observed anti-inflammatory effects were related to the inhibition of TNF-alpha, we also investigated the effect of etanercept, a TNF-alpha soluble receptor construct, on carrageenan-induced pleurisy. The treatment with etanercept (5 mg/kg subcutaneously 2 h before the carrageenan injection) reduces markedly both laboratory and histological signs of carrageenan-induced pleurisy. Our results showed that administration of etanercept resulted in the same outcome as that of deletion of the TNF-alphaR1 receptor, adding a new insight to TNF-alpha as an excellent target by therapeutic applications.

Combination of dexamethasone and etanercept reduces secondary damage in experimental spinal cord trauma.

The aim of our study was to evaluate the therapeutic efficacy of combination therapy with etanercept and dexamethasone (DEX) in vivo in experimental murine model of spinal cord trauma, which was induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. Spinal cord injury in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and cytokine production followed by recruitment of other inflammatory cells, production of inflammation mediators, tissue damage, apoptosis and disease. Treatment of the mice with etanercept (1.25 mg/kg) and DEX (0.025 mg/kg) when administered as a combination therapy but not as a single treatment significantly reduced the degree of (1) spinal cord inflammation and tissue injury (histological score), (2) infiltration of neutrophils (MPO evaluation), (3) inducible nitric oxide synthase, nitrotyrosine, and cytokines expression (tumor necrosis factor-alpha and interleukin-1 beta), (4) and apoptosis (Terminal deoxynucleotidyltransferase-mediated UTP end labeling staining, Fas-ligand expression and Bax and Bcl-2 expression). In a separate set of experiments we have also clearly demonstrated that the combination therapy significantly ameliorated the recovery of limb function (evaluated by motor recovery score). Taken together, our results clearly demonstrate for the first time that strategies targeting multiple proinflammatory pathways may be more effective than a single effector molecule for the treatment of spinal cord trauma.

Effects of etanercept, a tumour necrosis factor-alpha antagonist, in an experimental model of periodontitis in rats.

BACKGROUND AND PURPOSE: Etanercept is a tumour necrosis factor antagonist with anti-inflammatory effects. The aim of our study was to evaluate, for the first time, the therapeutic efficacy of in vivo inhibition of TNF-alpha in an experimental model of periodontitis. EXPERIMENTAL APPROACH: Periodontitis was induced in adult male Sprague-Dawley rats by placing a nylon thread ligature around the lower 1st molars. Etanercept was administered at a dose of 5 mg kg-1, s.c., after placement of the ligature. KEY RESULTS: Periodontitis in rats resulted in an inflammatory process characterized by oedema, neutrophil infiltration and cytokine production that was followed by the recruitment of other inflammatory cells, production of a range of inflammatory mediators, tissue damage, apoptosis and disease. Treatment of the rats with etanercept (5 mg kg-1, s.c., after placement of the ligature) significantly reduced the degree of (1) periodontitis inflammation and tissue injury (histological score), (2) infiltration of neutrophils (MPO evaluation), (3) iNOS (the expression of nitrotyrosine and cytokines (eg TNF-alpha)) and (4) apoptosis (Bax and Bcl-2 expression). CONCLUSIONS AND IMPLICATIONS: Taken together, our results clearly demonstrate that treatment with etanercept reduces the development of inflammation and tissue injury, events associated with periodontitis.

Inhibition of glycogen synthase kinase-3beta attenuates the development of carrageenan-induced lung injury in mice.

BACKGROUND AND PURPOSE: Glycogen synthase kinase-3 (GSK-3) is a ubiquitous serine-threonine protein kinase that participates in a multitude of cellular processes and has recently been implicated in the pathophysiology of a number of diseases. The aim of this study was to investigate the effects of GSK-3beta inhibition in a model of acute inflammation. Here, we have investigated the effects of TDZD-8, a potent and selective GSK-3beta inhibitor, in a mouse model of carrageenan-induced pleurisy. EXPERIMENTAL APPROACH: Injection of carrageenan into the pleural cavity of mice elicited an acute inflammatory response characterized by: accumulation of fluid containing a large number of neutrophils (PMNs) in the pleural cavity, infiltration of PMNs in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate (NOx), prostaglandin E2 (PGE2), tumour necrosis factor-alpha, (TNF-alpha) and interleukin-1beta (IL-1beta). Furthermore, carrageenan induced an upregulation of the adhesion molecules ICAM-1 and P-selectin, iNOS, COX-2 as well as nitrotyrosine as determined by immunohistochemical analysis of lung tissues. KEY RESULTS: Administration of TDZD-8 (1, 3 or 10 mg kg(-1), i.p.), 30 min prior to injection of carrageenan, caused a dose-dependent reduction in all the parameters of inflammation measured. CONCLUSIONS AND IMPLICATIONS: Thus, based on these findings we propose that inhibitors of the activity of GSK-3beta, such as TDZD-8, may be useful in the treatment of various inflammatory diseases.

Gastric hepatoid adenocarcinoma with autophagy-related necrosis-like tumor cell death: report of a case.

A case of hepatoid adenocarcinoma of the stomach is presented. The characteristic features of the tumor are summarized on the basis of the authors' experience and the literature. Ultrastructural examination revealed patchy condensations of chromatin throughout the nucleus suggestive of necrosis-like programmed cell death (PCD). These nuclear alterations were associated with the occurrence of vacuoles and lipofuscins, conferring an autophagic phenotype to this PCD. Thus, the case reported here provides an example of autophagic-related necrosis-like PCD. Alternative PCDs are reviewed and their morphologic distinction is discussed.

Neuroprotective effects of Ginkgo biloba extract in brain ischemia are mediated by inhibition of nitric oxide synthesis.

We studied the effects of pre-treatment (15 days) with oral administration of Ginkgo biloba extract (Ph-Gb 37.5-150 mg/kg) on brain malonildialdehyde (MDA), brain edema, brain nitrite and nitrate and delayed neuronal death following transient cerebral ischemia in the Mongolian gerbil. Survival was not modified, however, pre-treatment with Ginkgo biloba significantly and in a dose-dependent way reduced post-ischemic brain MDA levels and post-ischemic brain edema. Delayed neuronal death in the CA1 of the hippocampus was attenuated by the highest dose of the extract. Increase of nitrite and nitrate was observed after cerebral ischemia in the hippocampus and it was dose-dependently reduced in animals pretreated with Ph-Gb, thus suggesting that neuroprotective effects of Ginkgo biloba may be due to an inhibitory action on nitric oxide formation.

Quantitation of argyrophilic nucleolar organizer regions in regenerating muscle fibers in Duchenne and Becker muscular dystrophies and polymyositis.

We have investigated the quantity of argyrophilic nucleolar organizer region (AgNOR) proteins in vastus lateralis muscle samples from 13 patients with Duchenne muscular dystrophy (DMD) (6 months-12 years), 9 with Becker muscular dystrophy (BMD) (13 months-36 years), 9 with polymyositis (PM) (8-77 years) and 10 normal subjects (5 months-32 years). AgNORs were visualized on 4-microm-thick cryostat sections and quantified according to the guidelines of the Committee on AgNOR Quantitation; statistical analysis was performed on the mean AgNOR area (NORA) values. The mean NORA values encountered in DMD (4.327+/-0.791 microm2), BMD (3.534+/-0.312 microm2) and PM (3.785+/-0.424 microm2) samples were significantly (P<0.001) higher than those of normal muscle (1.682+/-0.288 microm2); a value of P<0.001 was also obtained when NORA values found in DMD were compared with those of BMD or PM. In addition, when NORA values were exclusively calculated in regenerating myofibers in DMD, BMD and PM, no differences were appreciable. On the other hand, in non-regenerating myofibers, the NORA values showed a significant increase in DMD versus BMD and PM (P<0.001) as well as in each disease group versus controls. Our study documents that muscle diseases, such as DMD, BMD and PM in which regeneration is a constant finding, have a high rDNA transcriptional activity. In particular, our findings suggest that (1) regenerating nuclei behave in the same way in dystrophinopathies or PM; (2) virtually all nuclei, including quiescent-looking ones, are activated to realize an increased intracellular protein synthesis for proliferative and/or functional purposes; and (3) the quantity of AgNOR does not seem related to age of patients at the time of biopsy.

Immunohistochemical detection of lactoferrin in human astrocytomas and multiforme glioblastomas.

The presence of lactoferrin in astrocytomas, anaplastic astrocytomas and multiforme glioblastomas was determined by immunohistochemistry; the staining intensity and the percentage of neoplastic stained cells were graded and statistical analysis was performed by non-parametric methods. A moderate to strong diffuse immunoreactivity for lactoferrin was shown in glial elements of astrocytomas, while the positivity was progressively reduced in anaplastic astrocytomas and in multiforme glioblastomas, some of which were unstained; a highly significant difference was found between scores relative to astrocytomas and glioblastomas. We suggest that the lactoferrin may be produced by neoplastic astrocytes which permits a greater availability of iron for metabolic cellular processes. Alternatively, the cytoplasmic localization of lactoferrin in neoplastic astrocytes may be the consequence of defective or functionally impaired lactoferrin receptors at the cellular surface.