Cerebral palsy (CP) is the most frequent neurological disorder associated with perinatal injury o... more Cerebral palsy (CP) is the most frequent neurological disorder associated with perinatal injury of the developing brain. Major brain lesions associated with CP are white matter damage (WMD) in preterm infants and cortico-subcortical lesions in term newborns. Cell therapy is considered promising for the repair of brain damage. Human umbilical cord blood mononuclear cells (hUCB-MNCs) are a rich source of various stem cells that could be of interest in repairing perinatal brain damage. Our goal was to investigate the potential of hUCB-MNCs to prevent or repair brain lesions in an animal model of excitotoxic brain injury. We induced neonatal brain lesions using intracranial injections of ibotenate, a glutamate agonist, in 5-day-old rat pups. hUCB-MNCs were injected either intraperitoneally (i.p.) or intravenously (i.v.) soon or 24 h after ibotenate injection, and their neurological effects were assessed using histology and immunohistochemistry. hUCB-MNCs injected i.p. did not reach the systemic circulation but high amounts induced a significant systemic inflammatory response and increased the WMD induced by the excitotoxic insult. This effect was associated with a significant 40% increase in microglial activation around the white matter lesion. hUCB-MNCs injected i.v. soon or 24 h after the excitotoxic insult did not affect lesion size, microglial activation, astroglial cell density, or cell proliferation within the developing white matter or cortical plate at any concentration used. We demonstrated that hUCB-MNCs could not integrate into the developing brain or promote subsequent repair in most conditions tested. We found that the intraperitoneal injection of high amounts of hUCB-MNCs aggravated WMD and was associated with systemic inflammation.
Nitric oxide (NO) is a powerful vasodilator, involved in both physiological functions and pathoph... more Nitric oxide (NO) is a powerful vasodilator, involved in both physiological functions and pathophysiological alterations of various regulatory processes, for example, the maintenance of vascular tone and inflammation. The recently demonstrated impact of exogenous NO on the central nervous system extends its role under normal and pathological conditions. At times neuroprotective, at times neurotoxic, NO is capable of different effects depending upon the extent of cerebral damage, the cellular redox state, and the spatiotemporal coordinates and concentration at which it is synthesized. This review provides new insights into the short- and long-term effects of endogenous and exogenous NO in brain injury.
Various food constituents have been proposed as disease-modifying agents for Alzheimer's dise... more Various food constituents have been proposed as disease-modifying agents for Alzheimer's disease (AD), due to epidemiological evidence of their beneficial effects, and for their ability to ameliorate factors linked to AD pathogenesis, namely by: chelating iron, copper and zinc; scavenging reactive oxygen species; and suppressing the fibrillation of amyloid-beta peptide (Aβ). In this study, nine different food constituents (l-ascorbic acid, caffeic acid, caffeine, curcumin, (-)-epigallocatechin gallate (EGCG), gallic acid, propyl gallate, resveratrol, and α-tocopherol) were investigated for their effects on the above factors, using metal chelation assays, antioxidant assays, and assays of Aβ42 fibrillation. An assay method was developed using 5-Br-PAPS to examine the complexation of Zn(II) and Cu(II). EGCG, gallic acid, and curcumin were identified as a multifunctional compounds, however their poor brain uptake might limit their therapeutic effects. The antioxidants l-ascorbic ac...
Tc-99m P280 (a symmetrical synthetic dimer of 2 identical peptide monomers containing an RGD mime... more Tc-99m P280 (a symmetrical synthetic dimer of 2 identical peptide monomers containing an RGD mimetic sequence) is a radiolabeled peptide undergoing clinical trials for use in imaging activated platelets. We investigated the biodistribution and dosimetry of intravenous Tc-99m P280 by serial determination of blood, urine and scintigraphic regional activity. Ten normal volunteers (6 male, 4 female, age 44 ± 7)
International journal of pharmaceutics, Jan 6, 2009
The aim of the study was to prepare cationic ISCOMs using cationic derivatives of the saponin Qui... more The aim of the study was to prepare cationic ISCOMs using cationic derivatives of the saponin Quil A. The polyamines ethylenediamine, spermidine and spermine were conjugated with the glucuronic acid moiety of Quil A. The aqueous solubility of the derivatives increased with decreasing pH, and the pK(a) values were between 6 and 7. The CMCs of the ionised derivatives were around 0.5-1.0 mg/mL. Using the method of hydration of freeze-dried monophase systems, the interaction of each of the Quil A derivatives with phosphatidylcholine and cholesterol, at a mass ratio of 4:4:2 and a pH of 3 and 7.4, was investigated. A few ISCOM-like structures were present in the systems prepared at pH 7.4, hence the ternary system of Quil A spermine derivative, phosphatidylcholine and cholesterol was further investigated at pH 7.4 using a variety of mass ratios. A relatively high number of cationic ISCOM-like structures were observed at the mass ratio of 6:2:2. These ISCOM-like structures were less homog...
Genome function is dynamically regulated in part by chromatin, which consists of the histones, no... more Genome function is dynamically regulated in part by chromatin, which consists of the histones, non-histone proteins and RNA molecules that package DNA. Studies in Caenorhabditis elegans and Drosophila melanogaster have contributed substantially to our understanding of molecular mechanisms of genome function in humans, and have revealed conservation of chromatin components and mechanisms. Nevertheless, the three organisms have markedly different genome sizes, chromosome architecture and gene organization. On human and fly chromosomes, for example, pericentric heterochromatin flanks single centromeres, whereas worm chromosomes have dispersed heterochromatin-like regions enriched in the distal chromosomal…
LeuTech is a 99Tcm labelled, anti-CD15, IgM, murine monoclonal antibody shown to have high affini... more LeuTech is a 99Tcm labelled, anti-CD15, IgM, murine monoclonal antibody shown to have high affinity (Kd = 10(-11) M) for CD15 receptors (5.1 x 10(5)/cell) expressed on human neutrophils. LeuTech was injected directly, intravenously, and its efficacy in imaging infection in 46 consecutive patients was determined. Human anti-mouse antibody (HAMA) response was examined in 30 normal volunteers using a standard LeuTech dose reconstituted with decayed 99Tcm solution. There were 38 true positive, six true negative, and two false negative scans. Of the 38 positive images, 33 (92%) were positive within 10 min after injection of LeuTech. LeuTech accuracy in this group of patients was 96%, sensitivity 95%, specificity 100%, positive predictive value (PPV) 100%, and negative predictive value (NPV) 75%. No elevation of the HAMA titre was observed in any of the 30 normal volunteers and no adverse reaction was noted in any patient. LeuTech is a highly promising agent for rapid imaging of infectious foci.
Early and reliable diagnosis of colorectal cancer continues to be demanding and challenging. Colo... more Early and reliable diagnosis of colorectal cancer continues to be demanding and challenging. Colorectal cancer cells express Vasoactive Intestinal Peptide (VIP) receptors in high density. We have prepared a VIP analog (TP3654), labeled it with (99m)Tc, and evaluated it in experimental animals as an agent for imaging colorectal cancer. The tissue distribution of (99m)Tc-TP3654 has been compared with that of (111)In-DTPA-Octreotide and (99m)Tc-anti-CEA scan in nude mice bearing human colorectal cancer LS174T. Finally, pharmacokinetic and tissue distribution studies of (99m)Tc-TP3654 have been performed in four normal human volunteers. Data suggest that (99m)Tc-TP3654 can be prepared efficiently without loss of its receptor specificity and biological activity. Although the 24 hr tumor uptake of (99m)Tc-TP3654 in the animal model used was modest (0.21 +/- 0.07% I.D./g), the tissue distribution profile was more favorable than that of (111)In-DTPA-Octreotide or (99m)Tc-anti-CEA scan. Human studies indicated that (99m)Tc-TP3654 had no adverse effect in any subject. Within 24 hours, approximately 70% of the injected dose cleared through the kidneys, and approximately 20% through the hepatobiliary system. In these non-fasting volunteers hepatobiliary clearance was slow and in cancer patients tumor uptake was rapid. Data suggest that (99m)Tc-TP3654 is a promising agent for imaging colorectal cancer.
ISCOMs have received much attention as vaccine adjuvants due to their immunostimulatory effects. ... more ISCOMs have received much attention as vaccine adjuvants due to their immunostimulatory effects. They are colloidal particles typically comprised of phospholipids, cholesterol and Quil A, a crude mixture of saponins extracted from the bark of Quillaja saponaria Molina. We have previously shown that ISCOMs can be prepared by ether injection wherein an ether solution of phospholipids and cholesterol in a mass ratio of 5:2 is injected into a solution of Quil A at a mass ratio of 7 lipids: 3 Quil A. The aim of this study was firstly to isolate and characterise discrete fractions of Quil A and secondly to investigate which of these fractions were able to form ISCOMs by the method of ether injection. Six fractions of Quil A were isolated by semi-preparative reverse phase high performance liquid chromatography (RP-HPLC) and characterised by analytical HPLC, liquid chromatography tandem mass spectrometry (LC-MS) and the qualitative Liebermann-Burchard and Molisch tests for triterpenoids and carbohydrates respectively. ISCOMs were subsequently prepared from the isolated fractions by the method of ether injection and the resulting preparations characterized by photon correlation spectroscopy (PCS) and negative stain transmission electron microscopy (TEM). The molecular weights of the major compounds in the fractions ranged from approximately 1200 to approximately 2300 Da; all fractions tested positive for triterpenoids and saccharides and four of the fractions were identified as QS-7, QS-17, QS-18 and QS-21 by analysis (LC-MS and analytical HPLC). Injection of ether solutions of lipids into aqueous solutions of QS-17, QS-18 or QS-21 all resulted in homogeneous ISCOM dispersions. The combination of lipids and QS-7 by ether injection produced lamellae and liposomes as the prominent structures and a minor amount of ISCOMs. The remaining two hydrophilic, low molecular weight fractions of Quil A did not produce ISCOMs, instead liposomes and helical structures predominated in the samples.
Vasoactive intestinal peptide (VIP) was modified at the C terminus with a spacer and four amino a... more Vasoactive intestinal peptide (VIP) was modified at the C terminus with a spacer and four amino acids to serve as a chelating moiety. The modified peptide, TP 3654, was labeled with Tc-99m and evaluated in normal volunteers, as well as in patients with a history of cancer. Renal clearance (67%) was the primary route of excretion, with approximately 20% of the radioactivity clearing through the hepatobiliary system. No adverse reaction was noted in any of the subjects and all, except one small, of the known lesions as seen by CT, MRI, Tc-99m-MIBI, or mammography were correctly identified within a few minutes of an i.v. injection of approximately 10 mCi of Tc-99m-TP 3654 (specific activity 11.3 x 10(3) Ci/m mol). The scans were in concordance in nine patients. In the remaining two, one with a visible mass in the neck from high grade spindle cell sarcoma and the other with a palpable mass in a breast from ductal epithelial hyperplasia, were localized only with Tc-99m-TP 3654, but not with Tc-99m-MIBI. Both malignancies are known to express VIP receptors. The VIP analog promises to be a nontoxic and reliable agent for imaging cancers in humans that express VIP receptors.
This study examined university teachers' perceptions of the role of humor in English as a Foreign... more This study examined university teachers' perceptions of the role of humor in English as a Foreign Language (EFL) teaching, teachers' practices of humor use, and teachers' preferences regarding humor types in the context of Vietnam. An ethnographic approach was employed in this study, combining observations, fieldnotes and interviews. The findings revealed that teachers acknowledged several beneficial functions of humor in EFL teaching. All teachers used humor in their teaching, or claimed that they did so. The three most preferred types of humor are humorous comments, jokes, and funny stories, employed to lighten the atmosphere and increase the teachers' immediacy. Teachers' perceptions about their practices and preferred types of humor provide insights into their readiness to adopt humor in the classroom. This research raises awareness of how humor can be integrated in language teaching and provides recommendations for effective classroom use.
Cerebral palsy (CP) is the most frequent neurological disorder associated with perinatal injury o... more Cerebral palsy (CP) is the most frequent neurological disorder associated with perinatal injury of the developing brain. Major brain lesions associated with CP are white matter damage (WMD) in preterm infants and cortico-subcortical lesions in term newborns. Cell therapy is considered promising for the repair of brain damage. Human umbilical cord blood mononuclear cells (hUCB-MNCs) are a rich source of various stem cells that could be of interest in repairing perinatal brain damage. Our goal was to investigate the potential of hUCB-MNCs to prevent or repair brain lesions in an animal model of excitotoxic brain injury. We induced neonatal brain lesions using intracranial injections of ibotenate, a glutamate agonist, in 5-day-old rat pups. hUCB-MNCs were injected either intraperitoneally (i.p.) or intravenously (i.v.) soon or 24 h after ibotenate injection, and their neurological effects were assessed using histology and immunohistochemistry. hUCB-MNCs injected i.p. did not reach the systemic circulation but high amounts induced a significant systemic inflammatory response and increased the WMD induced by the excitotoxic insult. This effect was associated with a significant 40% increase in microglial activation around the white matter lesion. hUCB-MNCs injected i.v. soon or 24 h after the excitotoxic insult did not affect lesion size, microglial activation, astroglial cell density, or cell proliferation within the developing white matter or cortical plate at any concentration used. We demonstrated that hUCB-MNCs could not integrate into the developing brain or promote subsequent repair in most conditions tested. We found that the intraperitoneal injection of high amounts of hUCB-MNCs aggravated WMD and was associated with systemic inflammation.
Nitric oxide (NO) is a powerful vasodilator, involved in both physiological functions and pathoph... more Nitric oxide (NO) is a powerful vasodilator, involved in both physiological functions and pathophysiological alterations of various regulatory processes, for example, the maintenance of vascular tone and inflammation. The recently demonstrated impact of exogenous NO on the central nervous system extends its role under normal and pathological conditions. At times neuroprotective, at times neurotoxic, NO is capable of different effects depending upon the extent of cerebral damage, the cellular redox state, and the spatiotemporal coordinates and concentration at which it is synthesized. This review provides new insights into the short- and long-term effects of endogenous and exogenous NO in brain injury.
Various food constituents have been proposed as disease-modifying agents for Alzheimer's dise... more Various food constituents have been proposed as disease-modifying agents for Alzheimer's disease (AD), due to epidemiological evidence of their beneficial effects, and for their ability to ameliorate factors linked to AD pathogenesis, namely by: chelating iron, copper and zinc; scavenging reactive oxygen species; and suppressing the fibrillation of amyloid-beta peptide (Aβ). In this study, nine different food constituents (l-ascorbic acid, caffeic acid, caffeine, curcumin, (-)-epigallocatechin gallate (EGCG), gallic acid, propyl gallate, resveratrol, and α-tocopherol) were investigated for their effects on the above factors, using metal chelation assays, antioxidant assays, and assays of Aβ42 fibrillation. An assay method was developed using 5-Br-PAPS to examine the complexation of Zn(II) and Cu(II). EGCG, gallic acid, and curcumin were identified as a multifunctional compounds, however their poor brain uptake might limit their therapeutic effects. The antioxidants l-ascorbic ac...
Tc-99m P280 (a symmetrical synthetic dimer of 2 identical peptide monomers containing an RGD mime... more Tc-99m P280 (a symmetrical synthetic dimer of 2 identical peptide monomers containing an RGD mimetic sequence) is a radiolabeled peptide undergoing clinical trials for use in imaging activated platelets. We investigated the biodistribution and dosimetry of intravenous Tc-99m P280 by serial determination of blood, urine and scintigraphic regional activity. Ten normal volunteers (6 male, 4 female, age 44 ± 7)
International journal of pharmaceutics, Jan 6, 2009
The aim of the study was to prepare cationic ISCOMs using cationic derivatives of the saponin Qui... more The aim of the study was to prepare cationic ISCOMs using cationic derivatives of the saponin Quil A. The polyamines ethylenediamine, spermidine and spermine were conjugated with the glucuronic acid moiety of Quil A. The aqueous solubility of the derivatives increased with decreasing pH, and the pK(a) values were between 6 and 7. The CMCs of the ionised derivatives were around 0.5-1.0 mg/mL. Using the method of hydration of freeze-dried monophase systems, the interaction of each of the Quil A derivatives with phosphatidylcholine and cholesterol, at a mass ratio of 4:4:2 and a pH of 3 and 7.4, was investigated. A few ISCOM-like structures were present in the systems prepared at pH 7.4, hence the ternary system of Quil A spermine derivative, phosphatidylcholine and cholesterol was further investigated at pH 7.4 using a variety of mass ratios. A relatively high number of cationic ISCOM-like structures were observed at the mass ratio of 6:2:2. These ISCOM-like structures were less homog...
Genome function is dynamically regulated in part by chromatin, which consists of the histones, no... more Genome function is dynamically regulated in part by chromatin, which consists of the histones, non-histone proteins and RNA molecules that package DNA. Studies in Caenorhabditis elegans and Drosophila melanogaster have contributed substantially to our understanding of molecular mechanisms of genome function in humans, and have revealed conservation of chromatin components and mechanisms. Nevertheless, the three organisms have markedly different genome sizes, chromosome architecture and gene organization. On human and fly chromosomes, for example, pericentric heterochromatin flanks single centromeres, whereas worm chromosomes have dispersed heterochromatin-like regions enriched in the distal chromosomal…
LeuTech is a 99Tcm labelled, anti-CD15, IgM, murine monoclonal antibody shown to have high affini... more LeuTech is a 99Tcm labelled, anti-CD15, IgM, murine monoclonal antibody shown to have high affinity (Kd = 10(-11) M) for CD15 receptors (5.1 x 10(5)/cell) expressed on human neutrophils. LeuTech was injected directly, intravenously, and its efficacy in imaging infection in 46 consecutive patients was determined. Human anti-mouse antibody (HAMA) response was examined in 30 normal volunteers using a standard LeuTech dose reconstituted with decayed 99Tcm solution. There were 38 true positive, six true negative, and two false negative scans. Of the 38 positive images, 33 (92%) were positive within 10 min after injection of LeuTech. LeuTech accuracy in this group of patients was 96%, sensitivity 95%, specificity 100%, positive predictive value (PPV) 100%, and negative predictive value (NPV) 75%. No elevation of the HAMA titre was observed in any of the 30 normal volunteers and no adverse reaction was noted in any patient. LeuTech is a highly promising agent for rapid imaging of infectious foci.
Early and reliable diagnosis of colorectal cancer continues to be demanding and challenging. Colo... more Early and reliable diagnosis of colorectal cancer continues to be demanding and challenging. Colorectal cancer cells express Vasoactive Intestinal Peptide (VIP) receptors in high density. We have prepared a VIP analog (TP3654), labeled it with (99m)Tc, and evaluated it in experimental animals as an agent for imaging colorectal cancer. The tissue distribution of (99m)Tc-TP3654 has been compared with that of (111)In-DTPA-Octreotide and (99m)Tc-anti-CEA scan in nude mice bearing human colorectal cancer LS174T. Finally, pharmacokinetic and tissue distribution studies of (99m)Tc-TP3654 have been performed in four normal human volunteers. Data suggest that (99m)Tc-TP3654 can be prepared efficiently without loss of its receptor specificity and biological activity. Although the 24 hr tumor uptake of (99m)Tc-TP3654 in the animal model used was modest (0.21 +/- 0.07% I.D./g), the tissue distribution profile was more favorable than that of (111)In-DTPA-Octreotide or (99m)Tc-anti-CEA scan. Human studies indicated that (99m)Tc-TP3654 had no adverse effect in any subject. Within 24 hours, approximately 70% of the injected dose cleared through the kidneys, and approximately 20% through the hepatobiliary system. In these non-fasting volunteers hepatobiliary clearance was slow and in cancer patients tumor uptake was rapid. Data suggest that (99m)Tc-TP3654 is a promising agent for imaging colorectal cancer.
ISCOMs have received much attention as vaccine adjuvants due to their immunostimulatory effects. ... more ISCOMs have received much attention as vaccine adjuvants due to their immunostimulatory effects. They are colloidal particles typically comprised of phospholipids, cholesterol and Quil A, a crude mixture of saponins extracted from the bark of Quillaja saponaria Molina. We have previously shown that ISCOMs can be prepared by ether injection wherein an ether solution of phospholipids and cholesterol in a mass ratio of 5:2 is injected into a solution of Quil A at a mass ratio of 7 lipids: 3 Quil A. The aim of this study was firstly to isolate and characterise discrete fractions of Quil A and secondly to investigate which of these fractions were able to form ISCOMs by the method of ether injection. Six fractions of Quil A were isolated by semi-preparative reverse phase high performance liquid chromatography (RP-HPLC) and characterised by analytical HPLC, liquid chromatography tandem mass spectrometry (LC-MS) and the qualitative Liebermann-Burchard and Molisch tests for triterpenoids and carbohydrates respectively. ISCOMs were subsequently prepared from the isolated fractions by the method of ether injection and the resulting preparations characterized by photon correlation spectroscopy (PCS) and negative stain transmission electron microscopy (TEM). The molecular weights of the major compounds in the fractions ranged from approximately 1200 to approximately 2300 Da; all fractions tested positive for triterpenoids and saccharides and four of the fractions were identified as QS-7, QS-17, QS-18 and QS-21 by analysis (LC-MS and analytical HPLC). Injection of ether solutions of lipids into aqueous solutions of QS-17, QS-18 or QS-21 all resulted in homogeneous ISCOM dispersions. The combination of lipids and QS-7 by ether injection produced lamellae and liposomes as the prominent structures and a minor amount of ISCOMs. The remaining two hydrophilic, low molecular weight fractions of Quil A did not produce ISCOMs, instead liposomes and helical structures predominated in the samples.
Vasoactive intestinal peptide (VIP) was modified at the C terminus with a spacer and four amino a... more Vasoactive intestinal peptide (VIP) was modified at the C terminus with a spacer and four amino acids to serve as a chelating moiety. The modified peptide, TP 3654, was labeled with Tc-99m and evaluated in normal volunteers, as well as in patients with a history of cancer. Renal clearance (67%) was the primary route of excretion, with approximately 20% of the radioactivity clearing through the hepatobiliary system. No adverse reaction was noted in any of the subjects and all, except one small, of the known lesions as seen by CT, MRI, Tc-99m-MIBI, or mammography were correctly identified within a few minutes of an i.v. injection of approximately 10 mCi of Tc-99m-TP 3654 (specific activity 11.3 x 10(3) Ci/m mol). The scans were in concordance in nine patients. In the remaining two, one with a visible mass in the neck from high grade spindle cell sarcoma and the other with a palpable mass in a breast from ductal epithelial hyperplasia, were localized only with Tc-99m-TP 3654, but not with Tc-99m-MIBI. Both malignancies are known to express VIP receptors. The VIP analog promises to be a nontoxic and reliable agent for imaging cancers in humans that express VIP receptors.
This study examined university teachers' perceptions of the role of humor in English as a Foreign... more This study examined university teachers' perceptions of the role of humor in English as a Foreign Language (EFL) teaching, teachers' practices of humor use, and teachers' preferences regarding humor types in the context of Vietnam. An ethnographic approach was employed in this study, combining observations, fieldnotes and interviews. The findings revealed that teachers acknowledged several beneficial functions of humor in EFL teaching. All teachers used humor in their teaching, or claimed that they did so. The three most preferred types of humor are humorous comments, jokes, and funny stories, employed to lighten the atmosphere and increase the teachers' immediacy. Teachers' perceptions about their practices and preferred types of humor provide insights into their readiness to adopt humor in the classroom. This research raises awareness of how humor can be integrated in language teaching and provides recommendations for effective classroom use.
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