Metal complexes of ruthenium: a potential class of selective anticancer drugs

Metal complexes of ruthenium were subjected to a number of studies concerning their chemical behaviour and their potential role in medical applications. Particular emphasis was given to the examination of the antineoplastic properties of ruthenium complexes with a number of ligands of biological interest. The possibility of obtaining compounds of potential value in the chemotherapeutic approach to neoplastic disease is supported by observations that ruthenium compounds could interact with tumor cells better than with normal tissues. This interaction can be considered the result of the chemical characteristics of ruthenium ions which can confer much more selectivity than do the actually available and clinically used organic compounds or cis-dichlorodiammine-platinum (II). Thus, ruthenium-based compounds represent the way for introducing a new class of antitumor drugs endowed with a great potential for the management of human tumors.     

In vitro cell cycle arrest, in vivo action on solid metastasizing tumors, and host toxicity of the antimetastatic drug NAMI-A and cisplatin

The effects of NAMI-A (imidazolium trans-imidazoledimethyl sulfoxide-tetrachlororuthenate) are compared with cisplatin on tumor cells cultured in vitro at doses of 1 to 100 microM and on tumor metastases in vivo at maximum tolerated doses. Using mouse tumors that metastasize to the lungs, NAMI-A given i.p. for 6 consecutive days at 35 mg/kg/day, was effective independently of the tumor line being treated and of the stage of metastasis growth. Conversely, cisplatin (2 mg/kg/day for 6 days) was as effective as NAMI-A on MCa mammary carcinoma and TS/A adenocarcinoma and less effective than NAMI-A on Lewis lung carcinoma. Cisplatin reduced body weight gain and spleen weight during treatment and was much more toxic than NAMI-A on liver sinusoids, kidney tubules, and lung epithelium. In vitro NAMI-A caused a transient cell cycle arrest of tumor cells in the premitotic G2/M phase, whereas cisplatin caused a progressive dose-dependent disruption of cell cycle phases. Correspondingly, NAMI-A did not modify cell growth, whereas cisplatin caused a dose-dependent reduction of cell proliferation, as determined by sulforhodamine B test. Thus, NAMI-A, unlike cisplatin, is a potent agent for the treatment of solid tumor metastases as well as when these tumor lesions are in an advanced stage of growth. NAMI-A is endowed with a mechanism of action unrelated to direct tumor cell cytotoxicity, and such mechanism of action is responsible for a reduced host toxicity.     

Virtual reality measures in neuropsychological assessment: a meta-analytic review

Objective: Virtual reality-based assessment is a new paradigm for neuropsychological evaluation, that might provide an ecological assessment, compared to paper-and-pencil or computerized neuropsychological assessment. Previous research has focused on the use of virtual reality in neuropsychological assessment, but no meta-analysis focused on the sensitivity of virtual reality-based measures of cognitive processes in measuring cognitive processes in various populations. Method: We found eighteen studies that compared the cognitive performance between clinical and healthy controls on virtual reality measures. Results: Based on a random effects model, the results indicated a large effect size in favor of healthy controls (g = .95). For executive functions, memory and visuospatial analysis, subgroup analysis revealed moderate to large effect sizes, with superior performance in the case of healthy controls. Participants’ mean age, type of clinical condition, type of exploration within virtual reality environments, and the presence of distractors were significant moderators. Conclusions: Our findings support the sensitivity of virtual reality-based measures in detecting cognitive impairment. They highlight the possibility of using virtual reality measures for neuropsychological assessment in research applications, as well as in clinical practice.     

Two siblings with isolated GH deficiency due to loss-of-function mutation in the GHRHR gene: successful treatment with growth hormone despite late admission and severe growth retardation

Patients with growth hormone releasing hormone receptor (GHRHR) mutations exhibit pronounced dwarfism and are phenotypically and biochemically indistinguishable from other forms of isolated growth hormone deficiency (IGHD). We presented here two siblings with clinical findings of IGHD due to a nonsense mutation in the GHRHR gene who reached their target height in spite of late GH treatment. Two female siblings were admitted to our clinic with severe short stature at the age of 13.8 (patient 1) and 14.8 years (patient 2). On admission, height in patient 1 was 107 cm (-8.6 SD) and 117 cm (-6.7 SD) in patient 2. Bone age was delayed in both patients (6 years and 9 years). Clinical and biochemical analyses revealed a diagnosis of complete IGHD (peak GH levels on stimulation test was 0.06 ng/mL in patient 1 and 0.16 ng/mL in patient 2). Patients were given recombinant human GH treatment. Genetic analysis of the GH and GHRHR genes revealed that both patientscarried the GHRHR gene mutation p.Glu72X (c.214 G>T) in exon 3 in homozygous (or hemizygous) state. After seven years of GH treatment, the patients reached a final height appropriate for their target height. Final height was 151 cm (-1.5 SD) in patient 1 and 153 cm (-1.2 SD) in patient 2. In conclusion, genetic analysis is indicated in IGHD patients with severe growth failure and a positive family history. In spite of the very late diagnosis in these two patients who presented with severe growth deficit due to homozygous loss-of-function mutations in GHRHR, their final heights reached the target height.     

CDK1 Hyperphosphorylation Maintenance Drives the Time-course of G2-M Cell Cycle Arrest after Short Treatment with NAMI-A in Kb Cells

We investigated the molecular events of the ruthenium complex NAMI-A (0.1 mM for 1 h) on cell cycle G2-M arrest in KB carcinoma cells. Flow cytometry analysis showed a progressive accumulation of cells in S phase at 16 h, and in G2-M phase at 20 h after the end of treatment. NAMI-A pre-mitotic stop to cell proliferation was due to the maintenance of the phosphorylated, inactive, form of Cdk1, caused by the activation of the ATM/ATR checkpoint, as confirmed by the up-regulation and phosphorylation of Chk1. All these events are related to intracellular ruthenium accumulation, as confirmed by the lack of similar effects in cell lines unable to take the ruthenium compound up. Considering the dependence of NAMI-A cell cycle arrest on the dose and on the length of cell challenge, and considering the prolonged NAMI-A t1/2 in vivo in the lungs, we proved an even greater perturbation of the cell cycle regulating pathways in lung metastases of NAMI-A treated mice. The ex-vivo data confirm the interaction of the ruthenium compound NAMI-A with the ATM/ATR pathway, leading to the modulation of cell cycle regulating proteins, that can break the metastases cell cycle progression off.     

Risk factors for treatment failure in renal suppurative infections

There are conflicting results of published studies about prognostic value of various factors in purulent renal infections. The purpose of this study was to identify and quantify potential risk factors for early and late treatment failure in such infections. A retrospective review of 75 renal suppurative infections, at three tertiary Serbian Clinics of Urology, was conducted. We considered numerous potential risk factors in a multivariate analysis. This series was comprised of 49 women and 26 men, with mean age of 56.7 years. There were 38 and 37 patients who experienced successful and unfavorable early treatment outcome, respectively. Overall mortality rate was 9.3%. Comorbidity [odds ratio (OR) = 1.6], complex suppurative pathological findings (OR = 3.6), presence of Pseudomonas spp. (OR = 6.7), multiple bacterial strains (OR = 2.7), and positive culture itself (OR = 3.6) were the predictors of poor early prognosis. A urological intervention and presence of pyonephrosis significantly increased the chance for good initial outcome (OR = 0.32 and 0.37, respectively). In the late treatment failure analysis presence of comorbidities (OR = 5.8) and treatment complications (OR = 7.5) significantly increased chance for fatal outcome. Patients’ baseline health status and complexity of suppuration itself were the most important predictors of clinical outcomes. Surgical drainage dominated over antimicrobial therapy.     

The effects of the diabetes related soft tissue hand lesions and the reduced hand strength on functional disability of hand in type 2 diabetic patients

OBJECTIVES: The aim of the present study is to examine the effects of diabetes related soft tissue hand lesions such as Dupuytren's disease, trigger finger and limited joint mobility (LJM) and the reduced hand strength on the functional disability of the hand in type 2 diabetic patients. METHODS: Forty-four type 2 diabetic patients and 60 age and sex matched controls were included in the study. Subjects were examined for the presence of Dupuytren's disease, trigger finger and LJM. Grip strength was tested first with Jamar dynamometer followed by pinch strength measurements using by a manual pinchmeter. Electrophysiological studies were performed in both groups. Duru?z Hand Index (DHI) was used to assess the functional hand disability. RESULTS: The mean DHI score of the diabetics was significantly higher than controls (p<0.0001). Dupuytren's disease, trigger finger or LJM was not correlated with DHI in diabetic patients (p>0.05). The grip and pinch strengths were significantly lower in diabetic patients than the non-diabetic controls (p<0.05) and the grip and pinch strengths were negatively correlated with DHI in type 2 diabetic patients (p<0.001). CONCLUSION: Dupuytren's disease, trigger finger and LJM did not cause to functional disability of hand but low hand strength was found to cause functional disability of hand in our type 2 diabetic patients.