Central nervous system neurotoxicity associated with nelarabine in T-cell acute lymphoblastic leukemia.

INTRODUCTION: Nelarabine, a prodrug of arabinosylguanine has lineage-specific toxicity for T lymphoblasts and is used to treat refractory or relapsed T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma patients. The most commonly observed adverse effects associated with nelarabine are mainly hematological, i.e. neutropenia, anemia, and thrombocytopenia. Additionally, neurological, and gastrointestinal toxicities have been reported. Central nervous system neurotoxicity associated with nelarabine is very rare. CASE DESCRIPTION: A 37-year-old man patient diagnosed with T-cell acute lymphoblastic leukemia had experienced generalized tonic-clonic seizure which lasted for a few seconds and upper extremity weakness after three weeks of the nelarabine infusion. Computed tomography and magnetic resonance imaging have shown periventricular and nucleus caudatus abnormalities. Radiological findings suggested toxic leukoencephalopathy and acute infarct of right nucleus caudatus. MANAGEMENT AND OUTCOME: After high-dose steroids, intravenous immunoglobulin, and support treatment, his neurologic symptoms disappeared except for mild peroral numbness. However, radiological sequelae persisted despite clinical improvement. CONCLUSION: Physicians involved in the care of these patients who use nelarabine should be aware of the fact that cerebral toxicity of the nelarabine may occur especially in the presence of predisposing factors. It is crucial to monitor closely those patients receiving nelarabine and also those who have additional predisposing factors for neurotoxicity.

The Impact of Iron Overload in Acute Leukemia: Chronic Inflammation, But Not the Presence of Nontransferrin Bound Iron is a Determinant of Oxidative Stress.

In the literature, studies on the oxidant effects of nontransferrin bound iron [NTBI (eLPI assay)] during chemotherapy of acute lymphoblastic leukemia and acute myeloblastic leukemia are lacking. We established NTBI and oxidative stress determinants (OSD), iron parameters, high-sensitive C-reactive protein (hs-CRP) levels, liver tests, cumulative chemotherapeutic doses, and transfused blood in 36 children with acute leukemia throughout chemotherapy. These parameters were determined at the beginning and end of chemotherapy blocks (11 time points) and in 20 healthy children using enzyme-linked immunosorbent assay, and colorimetric and fluorometric enzymatic methods. In acute lymphoblastic leukemia, NTBI, OSD, and hs-CRP were higher than controls at 4/11, 7/11, and 9/11 time points (P<0.05). At 3 time points, NTBI and OSD concurrently increased. Ferritin, soluble transferrin receptor, serum iron, and transferrin saturation were higher than in controls at 5 to 11/11 time points (P<0.05). Those with NTBI had higher iron parameters than those without NTBI (P<0.05), but showed similar OSD, hs-CRP, liver enzymes, cumulative chemotherapeutics, and transfused blood (P>0.05). OSD did not correlate with NTBI, but correlated with hs-CRP. In conclusion, NTBI is a poor predictor of OSD in acute leukemia possibly because of the heterogeneity of NTBI and chronic inflammation. Further studies are needed to delineate the pathophysiology of these diseases.

Preparation of a Three-Dimensional Reduced Graphene Oxide Film by Using the Langmuir-Blodgett Method.

The Langmuir-Blodgett method has always been traditionally utilized in the deposition of two-dimensional structures. In this work, however, we employed the method to deposit three-dimensional reduced graphene oxide layers using an unconventional protocol for the first time. This was achieved by carrying out the dipping process after the collapse pressure or breaking point, which results in the formation of a highly porous three-dimensional surface topography. By varying the number of deposition layers, the porosity could be optimized from nanometer to micrometer dimensions. Employed as bioelectrodes, these three-dimensional reduced graphene oxide layers may allow improved adhesion and biocompatibility compared to the conventional two-dimensional surfaces. A larger number of pores also improves the mass transport of materials and therefore increases the charge-sustaining capacity and sensitivity. This could ultimately improve the performance of biofuel cells and other electrode-based systems.

The Notch pathway is a critical regulator of angiogenesis in a skin model of ischemia.

The Notch pathway is definitely required for normal vascular development. Although the contribution of Notch in postnatal angiogenesis is the focus of intense investigation, the implication of Notch in reparative neovascularization in the skin remains unexplored. In this study, we investigated Notch changes using a skin model of ischemia. Thirty Sprague-Dawley rats were divided into two groups. In the surgery group (n = 24), a caudally based dorsal skin flap was raised and sutured back into its initial position. In the control group, no surgical procedure was performed. Tissue biopsies were obtained at different time intervals. Tissue specimens were assessed for Delta-like ligand 4 (DLL4) and vascular endothelial growth factor (VEGF) gene expression by real-time polymerase chain reaction (PCR). Immunohistochemical staining was used for detection of DLL4 in tissue materials. Quantitative assessment of skin flap microvasculature was made. Compared with normoperfused tissue, VEGF and DLL4 expressions increased significantly (p < 0.01). Immunohistochemical analysis revealed weak and patchy expression of DLL4 in microvascular endothelial cells of normoperfused tissues. Conversely, DLL4 expression was upregulated in capillary endothelial cells after ischemia. In conclusion, in this study we have shown that the Notch ligand DLL4 is upregulated in skin tissue after ischemia. A deeper understanding of these fundamental principles will aid in the development of new avenues for the treatment of blood vessel-related skin pathologies.

Inhibition of the Notch Pathway Promotes Flap Survival by Inducing Functional Neoangiogenesis.

OBJECTIVE: The Notch pathway seems to function as an antiangiogenic factor, negatively regulating the sprouting effect of vascular endothelial growth factor (VEGF). This function is well defined in embryonic and tumor vasculature. However, little is known about its function in ischemia-induced angiogenesis. In the first part of this study, we investigated the role of Notch in reparative angiogenesis after ischemia. In the second part, we hypothesized that anti-Notch therapy will result in increased angiogenic sprouting. We analyzed the effect of Notch inhibition in the induction of angiogenic sprouting. METHODS: In the first part, we investigated the effect of ischemia on the Notch ligand delta-like ligand 4 (DLL4). Twenty rats were divided equally into 2 groups. In the surgery group, dorsal skin flap was used as model of ischemia. In the control group, no surgical procedure was performed. DLL4 and VEGF gene expressions were assessed. Immunohistochemical staining was used for detection of DLL4 in tissue materials. Plasma levels of VEGF and DLL4 were measured. In the second part, we investigated the effect of Notch inhibition using a gamma-secretase inhibitor (GSI) on inducing neoangiogenesis. Twenty rats were assigned to 2 equal groups. In all animals, dorsal skin flap was raised and sutured back into its bed. Animals in the GSI-treated group received GSI intravenously after surgery for 3 days. Saline was administered in the control group. Necrotic area measurements, microangiography, and histologic evaluations were performed to compare groups. RESULTS: In the first part, VEGF and DLL expressions increased in ischemic tissues (P < 0.01). Immunohistochemical analysis revealed that DLL4 expression was upregulated in capillary endothelial cells after ischemia. Plasma levels for VEGF and DLL4 were higher in the animals that underwent surgery (P < 0.01). In the second part, GSI treatment resulted in higher flap survival rates (P < 0.05). Microscopic analysis exhibited increase in the number of microvascular structures after GSI treatment (P < 0.05). Microangiographic evaluation showed that neovascularization increased in the GSI-applied flaps. CONCLUSIONS: We present an evidence for the importance of the Notch pathway in the regulation of ischemia-induced angiogenesis. Notch inhibition promotes flap survival by creating a neovasculature that has an increase in vascular density.

Improving Clinician Confidence in Insulin Prescriptions at Discharge for Individuals With Newly Diagnosed Type 1 Diabetes.

Background In a questionnaire, we found that pediatric clinicians at Basildon and Thurrock University Hospital (BTUH) have low confidence levels in prescribing multiple daily injections (MDI) for newly diagnosed pediatric patients with type 1 diabetes mellitus. We designed and evaluated locally tailored prescription guidance to improve confidence in MDI discharge prescriptions for pediatric doctors of all grades. Methods We designed a prescription guidance tool by adapting existing local guidelines to improve clinician familiarity with MDI prescriptions and prevent prescription errors. The intervention was delivered in a single pediatric unit to doctors of all levels. Feedback was collected, and the clinicians' confidence in their MDI prescriptions was evaluated before and after the intervention. Questionnaires were distributed to all pediatric doctors within the unit to assess their confidence in prescribing MDIs using a five-point Likert Scale. Furthermore, the questionnaires aimed to determine whether clinicians regularly consulted the existing local guidelines. Local guidelines were adapted in consultation with the local pediatric diabetic multidisciplinary team (MDT) and with reference to the East of England Pediatric Diabetes Network to present MDI guidance in a more concise format, which includes an example MDI discharge medication checklist. Following approval by the local guidelines management group, additional changes were made to enhance the practicality and accessibility of the discharge prescription guidance for clinicians. These guidelines were distributed to the pediatric MDT via email and displayed in visible areas of the department. Results Out of the 13 doctors surveyed, 10 provided pre- and post-intervention feedback (77%). Statistical significance was calculated using unpaired t-tests. Ninety percent of pediatric doctors routinely refer to local guidelines for guidance on MDI prescriptions. However, 50% of respondents felt that existing local guidelines were not easily accessible, given the time and effort required to locate them. The mean confidence score for completing MDI prescriptions at discharge before the intervention was 1.9 (SD: 0.83). After the intervention, it increased to 4 (SD: 0.63) (95% CI: 2.79-1.41, p<0.0001). Ninety percent of pediatric doctors felt that the design and display of the MDI guidelines optimized patient care. Conclusions Following the presentation of the project at a local audit and quality improvement (QI) meeting, the adapted guidelines were included in the junior doctor induction program at BTUH and made accessible on the local intranet. The production of locally tailored prescription guidance for MDI prescriptions at discharge has led to an increase in the confidence of pediatric doctors when writing their prescriptions. We aimed to continue updating this guidance as necessary and making further developments to enhance clinician confidence.

Determination of trace metals in airborne particulate matter of Kuala Terengganu, Malaysia.

Results from the present study in Kuala Terengganu, Malaysia indicated a significant spatial variation but generally the total suspended particulate concentrations (mean = 17.2-148 microg/m(3)) recorded were below the recommended Malaysia guideline for total suspended particulate (mean of 24-h measurement = 260 microg/m(3)). Some of the elemental composition of particulate aerosol is clearly affected by non crustal sources, e.g. vehicular emission sources. Based on correlation and enrichment analyses, the elements could be grouped into two i.e. Pb, Cd and Zn group with sources from vehicular emission (r > 0.6; enrichment factor > 10) and Al, Fe, Mn and Cr group that appears to be of crustal origin (r > 0.6; enrichment factor < 10). It can also be concluded that the mean levels of Pb (1 ng/m(3)), Cd (0.02 ng/m(3)) and Zn (2 ng/m(3)) in the study area are generally lower than other urban areas in Malaysia (Pb < 181 ng/m(3); Cd < 6 ng/m(3); Zn < 192 ng/m(3)).

Tapping into cyanobacteria electron transfer for higher exoelectrogenic activity by imposing iron limited growth.

The exoelectrogenic capacity of the cyanobacterium Synechococcus elongatus PCC7942 was studied in iron limited growth in order to establish conditions favouring extracellular electron transfer in cyanobacteria for photo-bioelectricity generation. Investigation into extracellular reduction of ferricyanide by Synechococcus elongatus PCC7942 demonstrated enhanced capability for the iron limited conditions in comparison to the iron sufficient conditions. Furtheremore, the significance of pH showed that higher rates of ferricyanide reduction occurred at pH 7, with a 2.7-fold increase with respect to pH 9.5 for iron sufficient cultures and 24-fold increase for iron limited cultures. The strategy presented induced exoelectrogenesis driven mainly by photosynthesis and an estimated redirection of the 28% of electrons from photosynthetic activity was achieved by the iron limited conditions. In addition, ferricyanide reduction in the dark by iron limited cultures also presented a significant improvement, with a 6-fold increase in comparison to iron sufficient cultures. Synechococcus elongatus PCC7942 ferricyanide reduction rates are unprecedented for cyanobacteria and they are comparable to those of microalgae. The redox activity of biofilms directly on ITO-coated glass, in the absence of any artificial mediator, was also enhanced under the iron limited conditions, implying that iron limitation increased exoelectrogenesis at the outer membrane level. Cyclic voltammetry of Synechococcus elongatus PCC7942 biofilms on ITO-coated glass showed a midpoint potential around 0.22 V vs. Ag/AgCl and iron limited biofilms had the capability to sustain currents in a saturated-like fashion. The present work proposes an iron related exoelectrogenic capacity of Synechococcus elongatus PCC7942 and sets a starting point for the study of this strain in order to improve photo-bioelectricity and dark-bioelectricity generation by cyanobacteria, including more sustainable mediatorless systems.

Application of frequency-domain Fluorescence Lifetime Imaging Microscopy as a quantitative analytical tool for microfluidic devices.

We describe the application of wide-field frequency domain Fluorescence Lifetime Imaging Microscopy (FLIM) to imaging in microfluidic devices. FLIM is performed using low cost, intensity modulated Light Emitting Diodes (LEDs) for illumination. The use of lifetime imaging for quantitative analysis within such devices is demonstrated by mapping the molecular diffusion of iodide ions across a microchannel.

FCN2 c.772G>T polymorphism is associated with chronic adenoiditis and/or tonsillitis, but not -4 A>G and -602 G>A.

OBJECTIVE: Ficolins are complement activating peptides that play a role in the initial host defense against infectious pathogens. In the present study, we investigated the relationship between single nucleotide polymorphisms (SNPs) in the ficolin 2 gene (FCN2) and chronic adenotonsillitis in pediatric cases. STUDY DESIGN: Case-control study. METHODS: A total of 101 pediatric patients diagnosed with chronic adenotonsillitis and 100 healthy children were enrolled in the study. Genotypes of FCN2 promoter SNPs - 602 G>A and -4 A>G, and the exonic SNP c.772G>T were determined by light SNP assay after realtime PCR analysis using genomic DNA samples obtained from peripheral blood samples of all participants. RESULTS: Of the 101 chronic tonsillitis patients, 38 were girls and 63 were boys; the mean age was 5.2 ± 2.3 years. The c.772G>T SNP frequency was significantly higher in chronic adenotonsillitis cases compared to the control group (p = 0.00); however, no significant difference was determined at positions -602 G>A or -4 A>G (p > 0.05). CONCLUSIONS: The FCN2 c.772G>T genotype appears to be associated with predisposition to chronic adenotonsillitis in the pediatric age group. This nucleotide change is likely to influence the level of gene expression and contribute to the development of disease.

Association between liver fibrosis and coronary heart disease risk in patients with nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is being increasingly recognized as the most common cause of chronic liver disease worldwide. It has been shown that NAFLD in adults is associated with increased risk of coronary heart disease (CHD). Because of the limitations of liver biopsy, noninvasive scoring indexes such as the NAFLD fibrosis score (NFS) were developed. The Framingham risk score (FRS) provides an estimate of CHD risk. In our study we aimed to investigate whether the severity of liver fibrosis estimated with the NFS is associated with a higher risk of CHD among individuals with ultrasonography-diagnosed NAFLD. STUDY: A total of 155 patients and controls (81 patients with NAFLD and 74 controls) with ages ranging from 18 to 70 years were enrolled in this cross-sectional prospective study. Demographic, anthropometric, clinical, and laboratory data were obtained from each individual. The NAFLD patients were divided into subgroups on the basis of the severity of fatty liver. The FRS and NFS were adopted to predict the risk of CHD and the severity of hepatic fibrosis. RESULTS: In our study, we found that the FRS was higher in NAFLD patients than in controls (P<0.05). According to the FRS category, NFSs were higher in the intermediate/high probability CHD risk group in NAFLD (P<0.05). In multiple models, only age, sex, cholesterol, and HDL were independently associated with intermediate/high CHD risk (P<0.05). We also found a positive correlation between the NFS and the FRS (r=0.373, P<0.001). The optimum NFS cutoff point for identifying intermediate/high CHD risk in NAFLD patients was -2.1284, with a sensitivity and specificity of 95.20 and 48.30%, respectively. The predictive performance of the NFS in the determination of intermediate/high CHD risk in NAFLD patients was found to be 72% based on the area under the curve value. CONCLUSION: The FRS is associated with the NFS in NAFLD. The assessment of liver fibrosis may be useful for the risk stratification of CHD in the absence of liver biopsy in clinical practice.

Lack of association of matrix metalloproteinase-9 promoter gene polymorphism in obstructive sleep apnea syndrome.

PURPOSE: Obstructive sleep apnea syndrome (OSAS) is a public health problem. There is an effort to establish the genetic contributions to the development of OSAS. One is matrix metalloproteinases, extracellular matrix degrading enzymes related to systemic inflammation. However, the impact of matrix metalloproteinase-9 (MMP-9) genotypes on the development of OSAS is unknown. Our aim was to determine whether MMP-9 single nucleotide polymorphism (SNP) (MMP-9 -1562C > T) is related to susceptibility to OSAS. MATERIAL AND METHODS: A total of 106 patients with a history of sleep apnea and 88 controls without a history of sleep apnea were enrolled in this study. Genotypes were determined by restriction fragment length polymorphism analyses after polymerase chain reaction. RESULTS: Genotypes and allele frequencies of the MMP-9 -1562C > T SNP was not statistically different between the patient and control groups (p > 0.05). There was a statistical association between apnea-hypopnea index (AHI) and body mass index (BMI), and also between AHI and neck circumference (p < 0.001). There was no association among the genotypes and AHI, neck circumference, or BMI (p > 0.05). CONCLUSIONS: We found no association between MMP-9 -1562C > T SNP and OSAS. Studies to investigate the role of other polymorphisms and expression of MMP-9 gene will provide more information.

An unusual cause of factitious arthritis.

Septic arthritis and toxic synovitis are clinical conditions that can develop in association with various causes and involve symptoms such as pain, swelling, redness, sensitivity and restricted movement in the joint. A 42-year-old male presented to the emergency department with severe joint pain and nausea after injecting a 1-cc mixture of turpentine oil, eucalyptus oil, mint oil and thyme oil, which he purchased from an alternative medicine store, into his right knee with a syringe because of chronic knee pain. Ballottement and sensitivity were present at physical examination. Knee puncture yielded 60 cc of cloudy fluid. There was no growth in the material obtained. Improvement was observed following subsequent arthroscopic washing of the joint space and IV antibiotherapy, and the patient was discharged on day 21 of hospitalization with oral antibiotic and analgesic therapy. Intra-articular injection of foreign bodies into the knee joint space for therapeutic purposes, as in this case report, is a very rare occurrence, but may lead to potentially complicated arthritis.