The role of UV-radiation in the development of conjunctival malignant melanoma

PURPOSE: To investigate the possible role of UV-radiation in the development of conjunctival malignant melanoma. N-ras mutations are frequently found in cutaneous melanomas of sun-exposed body areas. UV-radiation is thought to induce mutations in the N-ras gene, that convert these genes into active oncogenes. The presence of N-ras mutations has been considered an indicator for UV-exposure in the development of melanomas on sun-exposed body sides. METHODS: We analyzed six paraffin-embedded conjunctival melanomas for mutations of the N-ras gene. Codons 12, 13 and 61 were amplified using polymerase chain reaction and sequenced. RESULTS: We could not detect point mutations of the N-ras gene in our samples. CONCLUSION: Since we could not find deviations from the wild type sequence in the N-ras gene, our study does not support UV-exposure as being causative in the development of conjunctival melanoma.     

Phase I study of Datelliptium chloride,hydrochloride given by 24-h continuous intravenous infusion

Summary Datelliptium chloride, hydrochloride (SR 95 156B, NSC 626718X, DHE) was studied in a phase I trial of escalating doses given on a single 24-h continuous intravenous infusion schedule. Doses were escalated from 40 to 500 mg/m² in 19 patients who received a total of 24 courses. Courses were repeated after a minimal interval of 3 weeks. Local venous toxicity occurred at low doses (100 mg/m²) and was circumvented by the use of a central venous access for higher doses. Other clinical adverse events occurred (330 mg/m²), including moderate nausea and vomiting, mild diarrhea, dry mouth, neuropsychiatric manifestations, and fatigue. All of these side effects were reversible and none was dose-limiting. The dose-limiting toxicity was related to hepatic laboratory-test abnormalities in the form of reversible elevations of levels of serum bilirubin and liver enzymes at doses of 330 mg/m². The maximum tolerated dose for this schedule is 500 mg/m². Hematologic toxicity was minimal and non-dose-limiting. Neither drug-related deaths nor objective complete or partial responses were observed. However, a minor response and a long-term disease stabilization were obtained.     

Combination of ventilator care bundle and regular oral care with chlorhexidine was associated with reduction in ventilator associated pneumonia

BackgroundVentilator associated pneumonia (VAP) is an important source of morbidity and mortality in patients receiving mechanical ventilation. VAP is associated with prolongation of mechanical ventilation, ICU and hospital stay and increases in costs.MethodsQuality improvement project. Mechanically ventilated patients received oral care every 8 h with chlorhexidine 2%. A formal process was developed to evaluate compliance with the following ventilator bundle initiatives: head of the bed elevation to 30–45°, daily sedation vacation and assess the readiness to extubate, providing peptic ulcer disease prophylaxis and providing deep vein thrombosis prophylaxis (unless contraindicated).ResultsThe rate of VAP before starting the project, in the first 6 months of year 1431H, was 16.2 cases/1000 ventilator days. Six month after inception of the quality improvement project, the VAP rates decreased to 5.6 cases/1000 ventilator days at the end of 1431H, and at the end of 1432H, it was 5.5 cases/1000 ventilator days. This leads to significant reduction in mortality (adjusted according to APACHE II) from 23.4% to 19.1% (p value 0.024) and the length of stay in ICU from 9.7 to 6.5 days (p value 0.00002).ConclusionThe combination of regular oral hygiene with chlorhexidine 2% and rigorous implementation of ventilator care bundle was associated with significant reduction in VAP rate in mechanically ventilated patients. This has led to reduction in length of stay in ICU from 9.7 to 6.5 days and reduction in mortality from 23.4% to 19.1%.     

Dual targeting of the proteasome regulates survival and homing in Waldenstrom macroglobulinemia

Waldenström macroglobulinemia (WM) is an incurable low-grade B-cell lymphoma characterized by high protein turnover. We dissected the biologic role of the proteasome in WM using 2 proteasome inhibitors, NPI-0052 and bortezomib. We found that NPI-0052 inhibited proliferation and induced apoptosis in WM cells, and that the combination of NPI-0052 and bortezomib induced synergistic cytotoxicity in WM cells, leading to inhibition of nuclear translocation of p65NF-B and synergistic induction of caspases-3, -8, and -9 and PARP cleavage. These 2 agents inhibited the canonical and noncanonical NF-B pathways and acted synergistically through their differential effect on Akt activity and on chymotrypsin-like, caspaselike, and trypsinlike activities of the proteasome. We demonstrated that NPI-0052–induced cytotoxicity was completely abrogated in an Akt knockdown cell line, indicating that its major activity is mediated through the Akt pathway. Moreover, we demonstrated that NPI-0052 and bortezomib inhibited migration and adhesion in vitro and homing of WM cells in vivo, and overcame resistance induced by mesenchymal cells or by the addition of interleukin-6 in a coculture in vitro system. Theses studies enhance our understanding of the biologic role of the proteasome pathway in WM, and provide the preclinical basis for clinical trials of combinations of proteasome inhibitors in WM.     

Contributions of human hippocampal subfields to spatial and temporal pattern separation

We sought to explore the roles of the hippocampal subregions and adjacent medial temporal lobe regions in pattern separation and any differential contributions based on sequential or spatial information. Young adults performed an incidental‐encoding task on a sequence of four objects presented on the screen in one of eight locations while we collected high‐resolution functional MRI brain scans. We employed five trials of interest: first presentations, exact repetitions, lures in which the same objects were repeated in different locations (spatial lures), lures in which the same objects were presented in a different sequential order (sequential lures), and lures in which both the spatial location and sequence were changed (both lures). We found no evidence for spatial or sequential specialization in the hippocampal subfields, consistent with the hypothesis that the dentate gyrus acts as a universal pattern separator. Likewise, we did not observe specialization for the perirhinal or parahippocampal cortices for spatial or sequential information, though both regions show evidence for associative processing in this task. © 2013 Wiley Periodicals, Inc.     

Neurocognitive Outcome and White Matter Anisotropy in Childhood Acute Lymphoblastic Leukemia Survivors Treated with Different Protocols

Neurocognitive outcome affects the quality of life of ALL survivors. This study is aimed to assess the prevalence of neurocognitive dysfunction by psychometric and imaging tools in survivors of childhood ALL, treated with 3 different protocols and the effect of time elapsed since the end of chemotherapy. Sixty-two ALL survivors aged 6–18 years and treated in the period 1997–2007 and 60 healthy age and sex matched controls were subjected to neurocognitive testing using Wechsler Intelligence Scale for Children, Benton visual retention (BVRT) and Trail Making test (TMT), followed by diffusion weighed and diffusion tensor MRI for calculation of fraction anisotropy (FA). Survivors underwent revision of protocol and type of CNS therapy. Three different protocols were used: modified BFM 83, BFM 90, and CCG. Survivors treated with modified CCG protocol showed a significant decrease in all cognitive tests compared to control (p<.05); BFM 90 group had a significant lower IQ and longer TMT compared to both control and BFM 83 group and no significant difference was found in results of cognitive tests between BFM 83 and control group. Frontal FA was lower in CCG treated group compared to control, BFM 90 and BFM 83 groups (p<.05); meanwhile it was significantly lower in BFM 90 and BFM 83 groups compared to control group. We concluded that patients treated with modified CCG protocol showed the worst neurocognitive outcome among three assessed protocols. Frontal lobe FA might be an early marker for predicting the neurotoxicity in childhood ALL survivors.     

Effect of specific chemotherapy on the immune response and resistance to reinfection in experimental Schistosomiasis mansoni

Mice infected for 45 days with 120 Schistosoma mansoni cercariae and treated with praziquantel in a dose of 500 mg/kg for two consecutive days had a significant lower resistance to reinfection when challenged two weeks after treatment (45% compared to 88% in infected challenged untreated mice). In praziquantel-treated mice, the reduction in the per cent resistance was accompanied by a diminution in the size of hepatic granulomata and its in vivo correlate the delayed foot pad swelling. Moreover, the granuloma proportionate T-cell subset enumeration revealed a significant reduction in the number of T-helper cells. The humoral immune response as measured by the immediate foot pad swelling was not affected by praziquantel. Results reveal besides the diminution of the state in resistance to reinfection after praziquantel, possible involvement of egg-related pathology as a T-cell mediated reaction and as a mechanical obstacle in maintenance of this resistance.