Oral carcinogenicity study with nickel sulfate hexahydrate in Fischer 344 rats

Until now, existing data on the oral carcinogenicity of nickel substances have been inconclusive. Yet, the assessment of oral carcinogenicity of nickel has serious scientific and regulatory implications. In the present study, nickel sulfate hexahydrate was administered daily to Fischer 344 rats by oral gavage for 2 years (104 weeks) at exposure levels of 10, 30 and 50 mg NiSO(4).6H(2)O/kg. This treatment produced a statistically significant reduction in body weight of male and female rats, compared to controls, in an exposure-related fashion at 30 and 50 mg/kg/day. An exposure-dependent increase in mortality was observed in female rats. However, the overall study survival rate (males and females) was at least 25 animals per group (compliant with OECD guidelines) in the treated animals. Daily oral administration of nickel sulfate hexahydrate did not produce an exposure-related increase in any common tumor type or an increase in any rare tumors. One tumor type was statistically increased in a nickel sulfate-treated group compared to the study controls (keratoacanthoma in the 10 mg NiSO(4).6H(2)O/kg/day males), but there was no exposure-response relationship for this common tumor type. This study achieved sufficient toxicity to reach the Maximum Tolerated Dose (MTD) while maintaining a sufficiently high survival rate to allow evaluation for carcinogenicity. The present study indicated that nickel sulfate hexahydrate does not have the potential to cause carcinogenicity by the oral route of exposure in the Fischer 344 rat. Data from this and other studies demonstrate that inhalation is the only route of exposure that might cause concern for cancer in association with nickel exposures.     

Fertilization outcome,embryo development and birth after unstimulated IVM

Background/Purposes  

A common observation in oocyte in vitro maturation (IVM) cycles is poor embryo quality. However, no study was dedicated to assess zygote and early cleavage embryo quality in IVM cycles. The objective of this study is to analyze fertilization outcome, embryo development and the resulting pregnancy and births in unstimulated IVM cycles.     

Accessory atrioventricular myocardial pathways in mouse heart development: substrate for supraventricular tachycardias

Atrioventricular reentry tachycardia (AVRT) requiring an accessory atrioventricular pathway (AP) is the most common type of arrhythmia in the perinatal period. The etiology of these arrhythmias is not fully understood as well as their capability to dissipate spontaneously in the first year of life. Temporary presence of APs during annulus fibrosus development might cause this specific type of arrhythmias. To study the presence of APs, electrophysiological recordings of ventricular activation patterns and immunohistochemical analyses with antibodies specifically against atrial myosin light chain 2 (MLC-2a), Periostin, Nkx2.5, and Connexin-43 were performed in embryonic mouse hearts ranging from 11.5 to 18.5 days post-conception (dpc). The electrophysiological recordings revealed the presence of functional APs in early (13.5-15.5 dpc) and late (16.5-18.5 dpc) postseptated stages of mouse heart development. These APs stained positive for MLC-2a and Nkx2.5 and negative for Periostin and Connexin-43. Longitudinal analyses showed that APs gradually decreased in number (p = 0.003) and size (p = 0.035) at subsequent developmental stages (13.5-18.5 dpc). Expression of periostin was observed in the developing annulus fibrosus, adjacent to APs and other locations where formation of fibrous tissue is essential. We conclude that functional APs are present during normal mouse heart development. These APs can serve as transient substrate for AVRTs in the perinatal period of development.     

Anti-ganglioside antibody-induced tumor cell death by loss of membrane integrity

Gangliosides have been involved in multiple cellular processes such as growth, differentiation and adhesion, and more recently as regulators of cell death signaling pathways. Some of these molecules can be considered as tumor-associated antigens, in particular, N-glycolyl sialic acid-containing gangliosides, which are promising candidates for cancer-targeted therapy because of their low expression in normal human tissues. In this study, we provided the molecular and cellular characterization of a novel cell death mechanism induced by the anti-NGcGM3 14F7 monoclonal antibody (mAb) in L1210 murine tumor cell line but not in mouse normal cells (B and CD4(+) T lymphocytes) that expressed the antigen. Impairment of ganglioside synthesis in tumor cells abrogated the 14F7 mAb cytotoxic effect; however, exogenous reincorporation of the ganglioside did not restore tumor cell sensitivity to 14F7 mAb-induced cytotoxicity. 14F7 F(ab')(2) but not Fab fragments retained the cytotoxic capacity of the whole mAb. By contrary, other mAb, which recognizes N-glycolylated gangliosides, did not show any cytotoxic effect. These mAbs showed quite different capacities to bind NGcGM3-positive cell lines measured by binding inhibition experiments. Interestingly, this complement-independent cell death mechanism did not resemble apoptosis, because no DNA fragmentation, caspase activation, or Fas mediation were observed. However, NGcGM3 ganglioside-mediated 14F7 mAb-induced cell death was accompanied by cellular swelling, membrane lesion formation, and cytoskeleton activation, suggesting an oncosis-like phenomenon. This novel mechanism of cell death lets us to support further therapeutic approaches using NGcGM3 as a molecular target for antibody-based cancer immunotherapy.     

The effects of skin‐to‐skin contact during acute pain in preterm newborns

Background and purpose: Several promising non‐pharmacological interventions have been developed to reduce acute pain in preterm infants including skin‐to‐skin contact between a mother and her infant. However, variability in physiological outcomes of existing studies on skin‐to‐skin makes it difficult to determine treatment effects of this naturalistic approach for the preterm infant. The aim of this study was to test the efficacy of mother and infant skin‐to‐skin contact during heel prick in premature infants. Method: Fifty nine stable preterm infants (born at least 30 weeks gestational age) who were undergoing routine heel lance were randomly assigned to either 15min of skin‐to‐skin contact before, during and following heel prick (n=31, treatment group), or to regular care (n=28, control group). Throughout the heel lance procedure, all infants were assessed for change in facial action (NFCS), behavioral state, crying, and heart rate. Results: Statistically significant differences were noted between the treatment and control groups during the puncture, heel squeeze and the post phases of heel prick. Infants who received skin‐to‐skin contact were more likely to show lower NFCS scores throughout the procedure. Both groups of infants cried and showed increased heart rate during puncture and heel squeeze although changes in these measures were less for the treated infants. Conclusions: Skin‐to‐skin contact promoted reduction in behavioral measures and less physiological increase during procedure. It is recommended that skin‐to‐skin contact be used as a non‐pharmacologic intervention to relieve acute pain in stable premature infants born 30 weeks gestational age or older.     

ACCM/PALS haemodynamic support guidelines for paediatric septic shock: an outcomes comparison with and without monitoring central venous oxygen saturation

INTRODUCTION: The ACCM/PALS guidelines address early correction of paediatric septic shock using conventional measures. In the evolution of these recommendations, indirect measures of the balance between systemic oxygen delivery and demands using central venous or superior vena cava oxygen saturation (ScvO(2) > or = 70%) in a goal-directed approach have been added. However, while these additional goal-directed endpoints are based on evidence-based adult studies, the extrapolation to the paediatric patient remains unvalidated. OBJECTIVE: The purpose of this study was to compare treatment according to ACCM/PALS guidelines, performed with and without ScvO(2) goal-directed therapy, on the morbidity and mortality rate of children with severe sepsis and septic shock. DESIGN, PARTICIPANTS AND INTERVENTIONS: Children and adolescents with severe sepsis or fluid-refractory septic shock were randomly assigned to ACCM/PALS with or without ScvO(2) goal-directed resuscitation. MEASUREMENTS: Twenty-eight-day mortality was the primary endpoint. RESULTS: Of the 102 enrolled patients, 51 received ACCM/PALS with ScvO(2) goal-directed therapy and 51 received ACCM/PALS without ScvO(2) goal-directed therapy. ScvO(2) goal-directed therapy resulted in less mortality (28-day mortality 11.8% vs. 39.2%, p=0.002), and fewer new organ dysfunctions (p=0.03). ScvO(2) goal-directed therapy resulted in more crystalloid (28 (20-40) vs. 5 (0-20 ml/kg, p<0.0001), blood transfusion (45.1% vs. 15.7%, p=0.002) and inotropic (29.4% vs. 7.8%, p=0.01) support in the first 6 h. CONCLUSIONS: This study supports the current ACCM/PALS guidelines. Goal-directed therapy using the endpoint of a ScvO(2)> or =70% has a significant and additive impact on the outcome of children and adolescents with septic shock.     

Myiasis of the scalp due to Dermatobia hominis in a traveler returning from Brazil

This article describes a case of myiasis by Dermatobia hominis diagnosed in a young Italian man returning from a vacation through Brazil. Considering the increasing number of travels to tropical and subtropical areas, clinicians in nonendemic areas must think about the possibility of imported unusual infestations during their daily practice.