New iron chelators in anthracycline-induced cardiotoxicity

The use of anthracycline anticancer drugs is limited by a cumulative, dose-dependent cardiac toxicity. Iron chelation has long been considered as a promising strategy to limit this unfavorable side effect, either by restoring the disturbed cellular iron homeostasis or by removing redox-active iron, which may promote anthracycline-induced oxidative stress. Aroylhydrazone lipophilic iron chelators have shown promising results in the rabbit model of daunorubicin-induced cardiomyopathy as well as in cellular models. The lack of interference with the antiproliferative effects of the anthracyclines also favors their use in clinical settings. The dose, however, should be carefully titrated to prevent iron depletion, which apparently also applies for other strong iron chelators. We have shown that a mere ability of a compound to chelate iron is not the sole determinant of a good cardioprotector and the protective potential does not directly correlate with the ability of the chelators to prevent hydroxyl radical formation. These findings, however, do not weaken the role of iron in doxorubicin cardiotoxicity as such, they rather appeal for further investigations into the molecular mechanisms how anthracyclines interact with iron and how iron chelation may interfere with these processes.     

Effect of PJ-34 PARP-inhibitor on rat liver microcirculation and antioxidant status

BACKGROUND: Ischemia-reperfusion (I-R) injury during liver resection leads to the production of toxic free radicals and oxidants that influence the microcirculation. DNA single-strand breaks can be induced by these reactive species. In response to excessive DNA damage, PARP [poly(ADP-ribose) polymerase] becomes overactivated, which can lead to cellular ATP depletion and cell death. The aim of our study was to evaluate whether PARP is expressed in post-ischemic liver, and to examine the effect of the administration of PJ-34 PARP inhibitor on liver function, histopathology, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) reaction, and the oxidative state of the liver after injury. METHODS: Male Wistar rats (weighing 250 g) underwent 60 min of normothermic, segmental liver ischemia followed by 30 min of reperfusion. The animals (n = 45) were divided into three groups: sham operated; I-R (control) treated with saline; and PJ-34 pre-treated (10 mg/kg i.v.). Hepatic microcirculation was monitored by a laser Doppler flowmeter. The reperfusion was characterized as the integral of the reperfusion area (RA) and the maximal plateau (PM). Histological alterations, TUNEL-reaction, serum, and liver tissue antioxidant levels, as well as serum ALT and AST levels were measured. RESULTS: Upon reperfusion, the PJ-34 group had significantly (P < 0.05) higher flow rates than control groups (PM(PJ-34): 58%, PM(control): 37%; RA(PJ-34.): 48%, RA(control): 25%). At the end of the 30 min reperfusion, PJ-34 resulted in significantly (P < 0.05) lower serum ALT and AST levels and chemiluminescent intensity (free radicals) of the liver. The liver's free SH-group concentration and H-donor ability of the plasma was elevated in the PARP-inhibitor treated group. Positive staining for TUNEL, after PJ-34 pre-treatment was significantly increased (P < 0.05); in contrast, the control tissues were less positively stained for TUNEL but necrotic tissue was abundant. CONCLUSION: PARP plays a pathogenetic role in the deterioration of the hepatic microcirculation and promotes hepatocellular necrosis in liver reperfusion injury.     

Exploring the oral bacterial flora: current status and future directions

Oral Diseases (2010) 16 , 136–145 Objective: The oral cavity forms an indispensable part of the human microbiome, for its unique and diverse microflora distributed within various niches. While majority of these organisms exhibit commensalism, shifts in bacterial community dynamics cause pathological changes within oral cavity and distant sites. The aim of this review was to appraise the current and emerging methods of detecting bacteria of the oral cavity paying particular attention to the cultivation independent methods. Design: Literature pertaining to cultivation based and cultivation independent methods of oral bacterial identification was reviewed. Methods: The specific advantages and disadvantages of cultivation based, microscopic, immunological and metagenomic identification methods were appraised. Results: Because of their fastidious and exacting growth requirements, cultivation based studies grossly underestimate the extent of bacterial diversity in these polymicrobial infections. Culture independent methods deemed more sensitive in identifying difficult to culture and novel bacterial species. Conclusion: Apart from characterizing potentially novel bacterial species, the nucleic acid sequence data analyzed using various bioinformatics protocols have revealed that there are in excess of 700 bacterial species inhabiting the mouth. Moreover, the latest pyrosequencing based methods have further broadened the extent of bacterial diversity in oral niches.     

Transmandibular approach for upper cervical pathologies: report of 2 cases and review of the literature

In routine surgical practice, anterior approaches are not often used to treat upper cervical pathologies. Such lesions can be difficult to access surgically. This article describes 2 cases in which the transmandibular approach was used to address anterior upper cervical pathology. One case was a chordoma invading the C2-C3 vertebrae and the other case was atlanto-axial instability. Neurological examination revealed myelopathy in both cases. Each patient had already undergone occipito-cervical fusion at a different center and, thus, had limited neck extension and mouth-opening ability. In the first case, the tumor was totally excised. In the second, the dens was removed. We believe that the transmandibular approach is the best option for patients with limited neck mobility and restricted mouth-opening ability.     

A real-life observational study of the effectiveness of FACT in a Dutch mental health region

Background

Suicide is a statistically rare event, but devastating to those left behind and one of the worst possible outcomes associated with mental illness. Although a friend, family member or co-worker may be the first person to notice that a person is highly distressed, few have the knowledge and skills required to assist. Simple guidelines may help such a person to encourage a suicidal individual to seek professional help or decide against suicide.

Methods

This research was conducted using the Delphi methodology, a method of reaching consensus in a panel of experts. Experts recruited to the panels included 22 professionals, 10 people who had been suicidal in the past and 6 carers of people who had been suicidal in the past. Statements about how to assist someone who is thinking about suicide were sourced through a systematic search of both professional and lay literature. The guidelines were written using the items most consistently endorsed by all three panels.

Results

Of 114 statements presented to the panels, 30 were accepted. These statements were used to develop the guidelines appended to this paper.

Conclusion

There are a number of actions which are considered to be useful for members of the public when they encounter someone who is experiencing suicidal thoughts or engaging in suicidal behaviour. These guidelines will be useful in revision of curricula of mental health first aid and suicide intervention training programs. They can also be used by members of the public who want immediate information about how to assist a suicidal person.     

C1D is a major autoantibody target in patients with the polymyositis-scleroderma overlap syndrome

OBJECTIVE: To assess whether the recently discovered exosome-associated proteins MPP6, C1D, KIAA0052/hMtr4, hSki2, and hSki8 are targeted by autoantibodies, and to determine whether these autoantibodies are accompanied by antibodies directed to the established exosome-associated autoantigens PM-Scl-75 and PM-Scl-100. METHODS: Complementary DNAs encoding the recently identified human exosome-associated proteins were expressed as His-tagged fusion proteins in Escherichia coli cells. Sera obtained from patients with several different autoimmune diseases were analyzed for the presence of autoantibodies directed to these proteins, in an enzyme-linked immunosorbent assay (ELISA). The ELISA data obtained for C1D were confirmed by Western blot analysis, using recombinant C1D. RESULTS: All exosome-associated proteins were found to be targeted by autoantibodies, although the frequency with which such antibodies occurred in patient sera was relatively low, with the exception of anti-C1D antibodies. Autoantibodies recognizing C1D were detected in 7 of 30 patients (23%) with the polymyositis (PM)-scleroderma overlap syndrome; this frequency was similar to the frequencies for the established autoantigens PM-Scl-75c (27%) and PM-Scl-100 (23%). Importantly, several patients with the PM-scleroderma overlap syndrome had anti-C1D antibodies but no anti-PM-Scl antibodies. Anti-C1D autoantibodies were observed in only 2 of 204 patients with other diseases, including PM, dermatomyositis, and scleroderma. CONCLUSION: Our results demonstrate that the recently identified exosome-associated protein C1D is a major autoantigen in patients with the PM-scleroderma overlap syndrome and suggest that the use of recombinant C1D as an autoantibody target may aid in diagnosis of the PM-scleroderma overlap syndrome.