The effects of methylglyoxal-bis(guanylhydrazone) on spermine binding and transport in liver mitochondria

This study evaluated the effect of the anticancer drug methylglyoxal-bis(guanylhydrazone) (MGBG) on the binding of the polyamine spermine to the mitochondrial membrane and its transport into the inner compartment of this organelle. Spermine binding was studied by applying a new thermodynamic treatment of ligand-receptor interactions (Di Noto et al., Macromol Theory Simul 5: 165-181, 1996). Results showed that MGBG inhibited the binding of spermine to the site competent for the first step in polyamine transport; the interaction of spermine with this site, termed S1, also mediates the inhibitory effect of the polyamine on the mitochondrial permeability transition (Dalla Via et al., Biochim Biophys Acta 1284: 247-252, 1996). In the presence of 1 mM MGBG, the binding capacity and affinity of this site were reduced by about 2.6-fold; on the contrary, the binding capacity of the S2 site, which is most likely responsible for the internalization of cytoplasmic proteins (see Dalla Via et al., reference cited above), increased by about 1.3-fold, and its binding affinity remained unaffected. MGBG also inhibited the initial rate of spermine transport in a dose-dependent manner by establishing apparently sigmoidal kinetics. Consequently, the total extent of spermine accumulation inside mitochondria was inhibited. This inhibition in transport seems to reflect a conformational change at the level of the channel protein constituting the polyamine transport system, rather than competitive inhibition at the inner active site of the channel, thereby excluding the possibility that the polyamine and drug use the same transport pathway. Furthermore, it is suggested that, in the presence of MGBG, the S2 site is able to participate in residual spermine transport. MGBG also strongly inhibits deltapH-dependent spermine efflux, resulting in a complete block in the bidirectional flux of the polyamine and its sequestration inside the matrix space. The effects of MGBG on spermine accumulation are consistent with in vivo disruption of the regulator of energy metabolism and replication of the mitochondrial genome.     

Spontaneous Splenic Rupture in a Patient with Acute Lymphoblastic Leukemia of Burkitt Type

We describe a case of spontaneous splenic rupture occurred in a patient with acute lymphoblastic leukemia of Burkitt type before starting cytotoxic chemotherapy. Left hypochondrial pain radiating to the homolateral shoulder was the only clinical symptom. Emergency computed tomography showed splenic laceration and hemoperitoneum. The patient underwent immediate laparotomy with splenectomy and experienced an uneventful postoperative recovery. Eight days after surgery, chemotherapy could be administered and complete remission was achieved. Although spontaneous rupture of the spleen is rare in leukemia and related disorders, this diagnosis should be taken in account also when clinical symptoms are mild. Following immediate operative management, patients may completely recover and receive cytotoxic chemotherapy with substantial possibilities of achieving complete remission.     

Microcirculation in the healing of surgical wounds in the oral cavity

The aim of this research is to evaluate in vivo the characteristics of microcirculation after taking a biopsy sample from the oral mucosa. 20 patients were recruited to the study and all underwent an oral mucosa biopsy for the excision of benign neoformations. The modifications in the oral microcirculation were evaluated in vivo in correspondence to the surgical site through videocapillaroscopy at three different times: 30 min before the biopsy; 48 h after the biopsy; and 7 days after the biopsy. The statistical significance was checked with the Mann–Whitney U-test (P < 0.05). The analysis of videocapillaroscopic patterns showed statistically significant variations relative to the capillary loop density; the diameter of the outgoing loop; and the length of the capillary loop. In conclusion, the study describes a simple and reproducible model for the study of wound healing from a microcirculatory point of view.     

Implication of core beliefs about negative-self in neuroticism

Abstract

Objective: Core beliefs about negative-self are beliefs about self-deficiencies in basic aspects of human adaptation. Meanwhile, neuroticism is a personality trait characterised by negative emotionality, i.e., a tendency to react to stress with negative emotions. The present study tested the hypothesis that core beliefs about negative-self are implicated in neuroticism.

Methods: The subjects were 309 Japanese healthy volunteers. Core beliefs about negative-self were evaluated by the Brief Core Schema Scales, and neuroticism was evaluated by the NEO Personality Inventory-Revised.

Results: In both multiple regression analysis and structural equation modelling, higher neuroticism was strongly predicted by higher levels of core beliefs about negative-self.

Limitations: The present study cannot determine the causal relationship between core beliefs about negative-self and neuroticism, because of its cross sectional design.

Conclusions: The present study suggests that core beliefs about negative-self are deeply implicated in neuroticism.

• Key Points

• Implication of core beliefs about negative-self in neuroticism was examined.

• Neuroticism was predicted by higher levels of these core beliefs.

• These core beliefs may be involved in negative emotionality of neuroticism.

     

Clinical utility of novel biomarkers for cardiovascular disease risk stratification

Over the past few decades, a number of coronary artery disease (CAD) and cardiovascular disease (CVD) risk factors have been identified. The predictive power of “conventional” risk factors have been validated by observational, prospective and intervention studies. Nevertheless, all attempts to exactly predict the individual risk for CAD have failed, biased by a large number of incorrectly risk-classified subjects. To improve cardiovascular (CV) risk prediction, a large number of genetic and/or non-genetic biomarkers have been discovered and tested against the “classical” risk factors for their power to predict CV risk. Only few of them had a significant improvement over the predictive models. In this paper, the most investigated biomarkers will be discussed and the evidence of their use as predictors of CV will be questioned.     

Intestinal Inflammation in Rats Induces Metallothionein in Colonic Submucosa

The aim of the current study was to determine if induction of metallothionein (MT) via acute or chronic dietary zinc supplementation attenuates intestinal inflammation, and to investigate the relationship with site-specific intestinal MT determined by immunolocalization. Growing rats were assigned to zinc-deficient (ZD), acute zinc-treated (ZT), pair-fed, control or chronic Zn-supplemented (ZS) groups. Half the rats in each dietary group received 5% dextran sulphate sodium (DSS) in their drinking water for 4 days. DSS treatment produced acute intestinal inflammation in the colon only, however, dietary zinc deficiency, acute zinc treatment or chronic zinc supplementation did not alter the severity of ulceration. Serum zinc concentrations were attenuated in the DSS-challenged ZT and ZS groups suggesting that zinc was being utilized in some capacity in response to inflammation. DSS-challenge induced MT immunostaining in the colonic submucosa, however, MT was not associated with histological improvements in the present study. The site-specific MT induction in colonic submucosa during intestinal inflammation requires further clarification as a component of the host defense.     

Treatment with low-dose cytosine arabinoside followed by administration of macrophage colony-stimulating factor prolongs the survival of patients with RAEB, RAEB-T, or leukemic phase myelodysplastic syndrome: a pilot study

The treatment of patients with aggressive subclasses of myelodysplastic syndrome (MDS) remains a challenge. In an effort to improve the survival of patients with refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEB-t), or acute myelogenous leukemia transformed from MDS (MDS-AML), we conducted a small trial in which 28 such patients were treated with low-dose cytosine arabinoside (LDAraC) followed by administration of macrophage colony-stimulating factor (M-CSF). The overall rate of response to the treatment was 61%, including 39% with a complete response, which is higher than rates obtained in previous studies in which LDAraC alone was administered to patients with MDS. Median survival was 23.5 months in cases of RAEB, 16.7 months in cases of RAEB-t, and 19.7 months in cases of MDS-AML. The overall survival of the study group appeared to be prolonged in comparison with a historical control group of patients treated with LDAraC alone. It is suggested that M-CSF added to the administration of LDAraC plays an active role in the therapy. No therapy-related death occurred. Some unique actions of M-CSF were suggested in this trial. It is concluded that therapy with LDAraC + M-CSF is a useful treatment option for patients with aggressive subclasses of MDS and MDS-AML to provide better response and survival.