Labial talon cusp on maxillary central incisors: a rare developmental dental anomaly

Labial talon cusp, or dens evaginatus is a very rare dental anomaly of unclear etiology and significance. It can occur as an isolated finding or be associated with other dental anomalies or some syndromes. The present report describes two Caucasian males with labial talon cusp on maxillary permanent left central incisors. In both cases accessory cusp caused plaque accumulation and marginal gingivitis. One case displayed affected tooth to be in cross bite position causing occlusal trauma. No other dental anomalies in either case, neither association with some syndromes were noted. This rare anomaly requires careful dental and physical examination of the affected patient since its finding can be of clinical and genetic significance.     

OTUB1 modulates c‐IAP1 stability to regulate signalling pathways

The cellular inhibitor of apoptosis (c‐IAP) proteins are E3 ubiquitin ligases that are critical regulators of tumour necrosis factor (TNF) receptor (TNFR)‐mediated signalling. Through their E3 ligase activity c‐IAP proteins promote ubiquitination of receptor‐interaction protein 1 (RIP1), NF‐κB‐inducing kinase (NIK) and themselves, and regulate the assembly of TNFR signalling complexes. Consequently, in the absence of c‐IAP proteins, TNFR‐mediated activation of NF‐κB and MAPK pathways and the induction of gene expression are severely reduced. Here, we describe the identification of OTUB1 as a c‐IAP‐associated deubiquitinating enzyme that regulates c‐IAP1 stability. OTUB1 disassembles K48‐linked polyubiquitin chains from c‐IAP1 in vitro and in vivo within the TWEAK receptor‐signalling complex. Downregulation of OTUB1 promotes TWEAK‐ and IAP antagonist‐stimulated caspase activation and cell death, and enhances c‐IAP1 degradation. Furthermore, knockdown of OTUB1 reduces TWEAK‐induced activation of canonical NF‐κB and MAPK signalling pathways and modulates TWEAK‐induced gene expression. Finally, suppression of OTUB1 expression in zebrafish destabilizes c‐IAP (Birc2) protein levels and disrupts fish vasculature. These results suggest that OTUB1 regulates NF‐κB and MAPK signalling pathways and TNF‐dependent cell death by modulating c‐IAP1 stability.     

An analysis of the pollution problem in Slavonski Brod (eastern Croatia)

H2S, PM2.5, O3, NO2, SO2 and meteorological parameters such as temperature, relative humidity, precipitation, wind speed and wind direction were measured simultaneously in an eastern Croatian town called Slavonski Brod during the season winter/spring 2010. Emissions from the nearby cross-border (Bosnia and Herzegovina) oil refinery were identified as sources of temporary elevated concentrations of H2S. The maximum daily averages of PM2.5 concentrations during the winter period were as high as 240 microg m(-3) which is a value 10 times greater than the threshold prescribed by the World Health Organization. It is considered that the heating season, dense traffic, intense industrial activities and temperature inversion during stable weather conditions are prevailing contributors to higher winter concentrations of PM2.5. The results of the principal component analysis technique (PCA) have shown that lower air temperature, lower wind speed and higher relative humidity play a significant role in the winter pollution episodes. From a public health point of view, implementation of measures aimed at reducing the levels of H2S and PM2.5 should be considered.     

Pentadecapeptide BPC 157 and its effects on a NSAID toxicity model: diclofenac-induced gastrointestinal, liver, and encephalopathy lesions

AimsWe attempted to fully antagonize the extensive toxicity caused by NSAIDs (using diclofenac as a prototype).Main methodsHerein, we used the stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419), an anti-ulcer peptide shown to be efficient in inflammatory bowel disease clinical trials (PL 14736) and various wound treatments with no toxicity reported. This peptide was given to antagonize combined gastrointestinal, liver, and brain toxicity induced by diclofenac (12.5 mg/kg intraperitoneally, once daily for 3 days) in rats.Key findingsAlready considered a drug that can reverse the toxic side effects of NSAIDs, BPC 157 (10 μg/kg, 10 ng/kg) was strongly effective throughout the entire experiment when given (i) intraperitoneally immediately after diclofenac or (ii) per-orally in drinking water (0.16 μg/mL, 0.16 ng/mL). Without BPC 157 treatment, at 3 h following the last diclofenac challenge, we encountered a complex deleterious circuit of diclofenac toxicity characterized by severe gastric, intestinal and liver lesions, increased bilirubin, aspartate transaminase (AST), alanine transaminase (ALT) serum values, increased liver weight, prolonged sedation/unconsciousness (after any diclofenac challenge) and finally hepatic encephalopathy (brain edema particularly located in the cerebral cortex and cerebellum, more in white than in gray matter, damaged red neurons, particularly in the cerebral cortex and cerebellar nuclei, Purkinje cells and less commonly in the hippocampal neurons).SignificanceThe very extensive antagonization of diclofenac toxicity achieved with BPC 157 (μg-/ng-regimen, intraperitoneally, per-orally) may encourage its further use as a therapy to counteract diclofenac- and other NSAID-induced toxicity.     

c-IAP1 and c-IAP2 are critical mediators of tumor necrosis factor alpha (TNFalpha)-induced NF-kappaB activation

The inhibitor of apoptosis (IAP) proteins are a family of anti-apoptotic regulators found in viruses and metazoans. c-IAP1 and c-IAP2 are recruited to tumor necrosis factor receptor 1 (TNFR1)-associated complexes where they can regulate receptor-mediated signaling. Both c-IAP1 and c-IAP2 have been implicated in TNFalpha-stimulated NF-kappaB activation. However, individual c-IAP1 and c-IAP2 gene knock-outs in mice did not reveal changes in TNF signaling pathways, and the phenotype of a combined deficiency of c-IAPs has yet to be reported. Here we investigate the role of c-IAP1 and c-IAP2 in TNFalpha-stimulated activation of NF-kappaB. We demonstrate that TNFalpha-induced NF-kappaB activation is severely diminished in the absence of both c-IAP proteins. In addition, combined absence of c-IAP1 and c-IAP2 rendered cells sensitive to TNFalpha-induced cell death. Using cells with genetic ablation of c-IAP1 or cells where the c-IAP proteins were eliminated using IAP antagonists, we show that TNFalpha-induced RIP1 ubiquitination is abrogated in the absence of c-IAPs. Furthermore, we reconstitute the ubiquitination process with purified components in vitro and demonstrate that c-IAP1, in collaboration with the ubiquitin conjugating enzyme (E2) enzyme UbcH5a, mediates polymerization of Lys-63-linked chains on RIP1. Therefore, c-IAP1 and c-IAP2 are required for TNFalpha-stimulated RIP1 ubiquitination and NF-kappaB activation.     

Dynamic in prescribing antipsychotic drugs during five year period (2001-2005) in the Psychiatric Hospital Vrapce, Zagreb, Croatia

Aim of this study was to determine changes in prescribing antipsychotics during 5 year period in Psychiatric Hospital VrapEe. Data about type of antipsychotic medication, ward and gender were collected for all patients receiving antipsychotics on 1st of October. During 5 year period decrease in prescribing classical antipsychotics was observed while prescribing of atypical antipsychotics has shown increase. There was an increase in number of patients treated with combination of antipsychotics, while number of patients treated with clozapine remained the same. It was noticed that female patients were more often treated with atypical antipsychotics. Data for forensic and emergency ward was analyzed separately and trends similar to hospitals were noticed here. Rationalizing use of antipsychotics can decrease cost of treatment, decrease negative effects of antipsychotics and consequently improve the treatment. Through systematic studies of this type positive progress and changes in the prescribing of antipsychotics are possible.     

The inhibitor of apoptosis protein fusion c-IAP2.MALT1 stimulates NF-kappaB activation independently of TRAF1 AND TRAF2

The inhibitors of apoptosis (IAPs) are a family of cell death inhibitors found in viruses and metazoans. All members of the IAP family have at least one baculovirus IAP repeat (BIR) motif that is essential for their anti-apoptotic activity. The t(11, 18)(q21;q21) translocation fuses the BIR domains of c-IAP2 with the paracaspase/MALT1 (mucosa-associated lymphoid tissue) protein, a critical mediator of T cell receptor-stimulated activation of NF-kappaB. The c-IAP2.MALT1 fusion protein constitutively activates the NF-kappaB pathway, and this is considered critical to malignant B cell transformation and lymphoma progression. The BIR domains of c-IAP1 and c-IAP2 interact with tumor necrosis factor receptor-associated factors 1 and 2 (TRAF1 and TRAF2). Here we investigated the importance of TRAF1 and TRAF2 for c-IAP2.MALT1-stimulated NF-kappaB activation. We identified a novel epitope within the BIR1 domains of c-IAP1 and c-IAP2 that is crucial for their physical interaction with TRAF1 and TRAF2. The c-IAP2.MALT1 fusion protein associates with TRAF1 and TRAF2 using the same binding site. We explored the functional relevance of this interaction and established that binding to TRAF1 and TRAF2 is not required for c-IAP2.MALT1-stimulated NF-kappaB activation. Furthermore, gene ablation of TRAF2 or combined down-regulation of TRAF1 and TRAF2 did not affect c-IAP2.MALT1-stimulated signaling. However, TRAF1/2-binding mutants of c-IAP2.MALT1 still oligomerize and activate NF-kappaB, suggesting that oligomerization might be important for signaling of the fusion protein. Therefore, the t(11, 18)(q21;q21) translocation creating the c-IAP2.MALT1 fusion protein activates NF-kappaB and contributes to human malignancy in the absence of signaling adaptors that might otherwise regulate its activity.     

Inhibitor of Apoptosis Proteins (IAPs) and Their Antagonists Regulate Spontaneous and Tumor Necrosis Factor (TNF)-induced Proinflammatory Cytokine and Chemokine Production

Inhibitor of apoptosis proteins (IAPs) play a major role in determining whether cells undergo apoptosis in response to TNF as well as other stimuli. However, TNF is also highly proinflammatory through its ability to trigger the secretion of multiple inflammatory cytokines and chemokines, which is arguably the most important role of TNF in vivo. Indeed, deregulated production of TNF-induced cytokines is a major driver of inflammation in several autoimmune conditions such as rheumatoid arthritis. Here, we show that IAPs are required for the production of multiple TNF-induced proinflammatory mediators. Ablation or antagonism of IAPs potently suppressed TNF- or RIPK1-induced proinflammatory cytokine and chemokine production. Surprisingly, IAP antagonism also led to spontaneous production of chemokines, particularly RANTES, in vitro and in vivo. Thus, IAPs play a major role in influencing the production of multiple inflammatory mediators, arguing that these proteins are important regulators of inflammation in addition to apoptosis. Furthermore, small molecule IAP antagonists can modulate spontaneous as well as TNF-induced inflammatory responses, which may have implications for use of these agents in therapeutic settings.     

Drinking in adolescents--qualitative analysis

The aim of this paper was to explore alcohol consumption and the development of this habit in the adolescent population based on qualitative data from 59 anonymous essays written by high school students. We found that the most of adolescents had their first experiences with alcohol in the seventh or eighth grades. They reported that they usually drank alcohol to be happy, to relax, to be courageous in approaching the opposite sex, to fit into society, and to be popular. Factors affecting drinking are influence of peers, family and social attitude towards drinking, laws and enforcement of legislation. In further prevention programs, we must be able to demonstrate that "having a good time" does not mean drinking alcohol. Programs for the prevention of alcohol-related problems must begin by adolescence, including both sexes equally and can be achieved through a coordinated and intense public health effort.