DNA-targeted 1,2,4-benzotriazine 1,4-dioxides: potent analogues of the hypoxia-selective cytotoxin tirapazamine

Tirapazamine (TPZ, 1,2,4-benzotriazin-3-amine 1,4-dioxide) is a bioreductive hypoxia-selective cytotoxin, currently in phase II/III clinical trials in combination with radiotherapy and with cisplatin-based chemotherapy. We have prepared a series of 1,2,4-benzotriazine 1,4-dioxide (BTO) analogues of TPZ where a DNA-targeting chromophore is attached at the 3-position via a flexible linker. DNA binding affinity was modified through variation of the chromophore or the pK(a) of the linker chain. The association constants (K(DNA)) for calf thymus DNA ranged from 1 x 10(2) to 5.6 x 10(5) M(-1) (ionic strength of 0.01 M). DNA binding affinity was dependent on the presence of a positive charge, either in the linker chain or in the chromophore, and (for a series of 4-acridine carboxamide chromophore analogues) correlated strongly with linker chain pK(a). The efficacy of these BTOs in killing aerobic and hypoxic mouse SCCVII tumor cells in vitro was determined by clonogenic survival. Cytotoxicity was measured as the concentration required to reduce plating efficiency to 10% of controls (C(10)), and the hypoxic cytotoxicity ratio (HCR) for each BTO was calculated as C(10)(aerobic)/C(10)(hypoxic). BTOs bearing a positive charge showed increased hypoxic cytotoxicity (1.5-56-fold) compared to TPZ and mostly modest HCRs (8-51), but some excellent (>167 and 400) values. There was a strong correlation between K(DNA) and hypoxic cytotoxicity but no correlation between K(DNA) and HCR. Cytotoxicity in HT-29 human colon carcinoma cells, determined using IC(50) assays, showed similar relationships with a correlation between K(DNA) and hypoxic cytotoxicity but no correlation between K(DNA) and HCR. In this cell line, a higher proportion of compounds (7 of 11) had HCRs greater than or equal to that of TPZ. The data confirm that DNA targeting is a useful concept for increasing potency while maintaining hypoxic selectivity and provide a direction for the further development of DNA-targeted analogues of TPZ.     

A one-pot synthesis of (±)-(ring 13C6)-mandelic acid

A one-pot synthesis of (±)-(ring ¹³C₆)-mandelic acid is reported. [Ring ¹³C₆]-benzaldehyde was cyanosilylated with trimethylsilyl cyanide (TMSCN)/Znl₂. The resulting cyanosilylated adduct was hydrolyzed with concentrated hydrochloric acid without purification. The workup involves evaporation to dryness and extraction of the (±)-(ring ¹³C₆)-mandelic acid with hot benzene. After one crystallization, the synthesis produced an overall yield of 65% of (±)-(ring ¹³C₆)-mandelic acid that was about 98% pure by HPLC with UV detection.     

Global standard for the composition of infant formula: recommendations of an ESPGHAN coordinated international expert group

The Codex Alimentarius Commission of the Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO) develops food standards, guidelines and related texts for protecting consumer health and ensuring fair trade practices globally. The major part of the world's population lives in more than 160 countries that are members of the Codex Alimentarius. The Codex Standard on Infant Formula was adopted in 1981 based on scientific knowledge available in the 1970s and is currently being revised. As part of this process, the Codex Committee on Nutrition and Foods for Special Dietary Uses asked the ESPGHAN Committee on Nutrition to initiate a consultation process with the international scientific community to provide a proposal on nutrient levels in infant formulae, based on scientific analysis and taking into account existing scientific reports on the subject. ESPGHAN accepted the request and, in collaboration with its sister societies in the Federation of International Societies on Pediatric Gastroenterology, Hepatology and Nutrition, invited highly qualified experts in the area of infant nutrition to form an International Expert Group (IEG) to review the issues raised. The group arrived at recommendations on the compositional requirements for a global infant formula standard which are reported here.     

Effectiveness of mirror therapy on lower extremity motor recovery,balance and mobility in patients with acute stroke: A randomized sham-controlled pilot trial

Objective:

To evaluate the effectiveness of mirror therapy on lower extremity motor recovery, balance and mobility in patients with acute stroke.

Design:

A randomized, sham-controlled, assessor blinded, pilot trial.

Setting:

Inpatient stroke rehabilitation unit.

Subjects:

First time onset of stroke with mean post-stroke duration of 6.41 days, able to respond to verbal instructions, and Brunnstrom recovery stage 2 and above were enrolled.

Intervention:

Mirror therapy group performed 30 minutes of functional synergy movements of non-paretic lower extremity, whereas control group underwent sham therapy with similar duration. In addition, both groups were administered with conventional stroke rehabilitation regime. Altogether 90 minutes therapy session per day, six days a week, for two weeks duration was administered to both groups.

Outcome Measures:

Lower extremity motor subscale of Fugl Meyer Assessment (FMA), Brunnel Balance Assessment (BBA) and Functional Ambulation Categories (FAC).

Results:

Amongst the 22 patients included, equal number of patients participated in mirror group (N = 11) and control group (N = 11). Baseline variables were similar in both groups, except for Brunnstrom recovery stage. There was no statistical difference between groups, except for FAC. (FMA: P = 0.894; BBA: P = 0.358; FAC: P = 0.02). Significance was set at P < 0.05.

Conclusion:

Administration of mirror therapy early after stroke is not superior to conventional treatment in improving lower limb motor recovery and balance, except for improvement in mobility.Key Words: Acute stroke, balance, mobility, mirror therapy, motor recovery     

Antimicrobial Effect of Conventional Root Canal Medicaments vs Propolis against Enterococcus faecalis, Staphylococcus aureus and Candida albicans

Aim: To evaluate and compare antimicrobial effect of various root canal medicaments against Enterococcus faecalis, Staphylococcus aureus and Candida albicans. Materials and methods: Six root canal medicaments: 2% sodium hypochlorite (NaOCl), 2% chlorhexidine (CHX) Calcium hydroxide (Ca(OH)2), EDTA, MTAD and propolis and three microorganisms: Staphylococcus aureus, Enterococcus faecalis and Candida albicans were used. These strains were inoculated in brain heart infusion (BHI) and incubated at 37 degrees C for 24 hours. For the agar diffusion test (ADT), petri plates with 20 ml of BHI agar were inoculated with 0.1 ml of the microbial suspensions, using sterile swabs that were spread on the medium, obtaining growth injunction. Paper disks were immersed in the experimental solutions for 1 minute. Subsequently, four papers disks containing one of the substances were placed on the BHI agar surface in each agar plate. The plates were incubated at 37°C for 48 hours. The diameter of microbial inhibition was measured around the papers disks containing the substances. One way ANOVA followed by Tukey's post-hoc test were used. p-value >0.05 was considered statistically significant. Results: Propolis and other irrigants were found to be effective on C. albicans, S. aureus and E. faecalis. CHX and MTAD were found to be most effective amongst all the materials tested followed by propolis. Conclusion: Propolis showed antimicrobial activity against E. faecalis, S. aureus, C. albicans. It appears that propolis is an effective intracanal irrigant in eradicating E. faecalis and C. albicans. Clinical significance: Propolis is an effective intracanal irrigant in eradicating E. faecalis and C. albicans. It could be used as an alternative intracanal medicament. Keywords: Root canal medicaments, Enterococcus faecalis, Staphylococcus aureus, Candida albicans, Propolis. How to cite this article: Mattigatti S, Jain D, Ratnakar P, Moturi S, Varma S, Rairam S. Antimicrobial Effect of Conventional Root Canal Medicaments vs Propolis Against Enterococcus faecalis, Staphylococcus aureus and Candida albicans. J Contemp Dent Pract 2012;13(3):305-309. Source of support: Nil Conflict of interest: None declared.     

Progression of structural lung disease on CT scans in children with cystic fibrosis related diabetes

BackgroundDiabetes has a deleterious effect on clinical status in children with Cystic Fibrosis (CF). We hypothesized that children with CF Related Diabetes (CFRD) or Impaired Glucose Tolerance (IGT) would have more rapidly progressive lung disease based on chest computed tomography (CT) than those with normal glucose tolerance (NGT).MethodsIn a retrospective study we compared lung structure changes over time, as assessed by CT, in 34 CF children with CFRD, IGT or NGT. We then compared CT findings with changes in lung function.ResultsPercentage forced expiratory volume in 1 s (%FEV₁) remained stable over time with a mean (± SD) yearly change of ? 0.5% (± 3.9), ? 0.4% (± 2.3) and ? 0.85% (± 2.8) (p = 0.92) for the CFRD, IGT and NGT groups respectively. However, there was a mean (95%CI) increase in % CT score of 3.86%/year (1.77–5.95%), 1.59%/year (0.6–2.58%) and 1.09%/year (0.07–2.11%) (p = 0.023).ConclusionIn patients with CFRD, there was a more rapid progression of structural lung disease, compared to those who had NGT that was not reflected by change in lung function.