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1.
Int J Immunogenet ; 42(3): 204-7, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25809846

ABSTRACT

The two-nucleotide deletion recently detected in the mannose-binding lectin 2 gene in purebred and crossbred domestic pigs was not found among 68 wild boars representing 4 populations from Europe and Asia. This suggests that the deletion is a result of breeding and/or genetic drift/bottle necks.


Subject(s)
Mannose-Binding Lectin/genetics , Sus scrofa/genetics , Animals , Austria , Czech Republic , Gene Frequency , Haplotypes , INDEL Mutation , Japan , Molecular Sequence Data , Polymorphism, Single Nucleotide , Sequence Deletion , Sweden
3.
Immunogenetics ; 66(3): 171-84, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24477343

ABSTRACT

The mannose-binding lectins (MBLs) are central components of innate immunity, facilitating phagocytosis and inducing the lectin activation pathway of the complement system. Previously, it has been found that certain single-nucleotide polymorphisms (SNPs) in porcine MBL1 and MBL2 (pMBL1, pMBL2) affect mRNA expression, serum concentration, and susceptibility to disease, but the combinatory effect of pMBL1 and pMBL2 genotypes needs further elucidation. In the present study, pMBL1 and pMBL2 alleles, combined pMBL haplotypes, and MBL-A concentration in serum were analyzed in purebred Landrace (N = 30) and Duroc (N = 10) pigs. Furthermore, the combined pMBL haplotypes of 89 Piètrain × (Large White × Landrace) crossbred pigs were studied, and the genotypes of 67 crossbreds challenged with Escherichia coli were compared to their individual disease records. In the purebred animals, three non-synonymous SNPs and a two-nucleotide deletion were detected in the coding sequence of pMBL2. The two-nucleotide deletion was present at a frequency of 0.88 in the Landrace pigs and 0.90 in the Duroc pigs, respectively. In the crossbreds, the T allele of the SNP G949T in pMBL1-previously shown to have profound effect on MBL-A concentration even in the heterozygote condition-was detected in 47 % of the animals. Finally, an association was found between low-producing MBL genotypes and low body weight on the day of weaning in the same animals.


Subject(s)
Mannose-Binding Lectin/genetics , Sequence Deletion , Sus scrofa/genetics , Alleles , Animals , Base Sequence , Breeding , Gene Frequency , Genetic Association Studies , Haplotypes , Mannose-Binding Lectin/chemistry , Molecular Sequence Data , Open Reading Frames , Phenotype , Phylogeny , Polymorphism, Single Nucleotide , Promoter Regions, Genetic , Sus scrofa/classification
4.
Int J Immunogenet ; 40(2): 131-9, 2013 Apr.
Article in English | MEDLINE | ID: mdl-22672630

ABSTRACT

The single nucleotide polymorphism (SNP) G949T in the mannose-binding lectin ( MBL ) 1 gene has been associated with low MBL-A concentration in serum and detected at different frequencies in various European pig populations. However, the origin of this SNP is not known. Part of the MBL1 gene was sequenced in 12 wild boar/Large White crossbred pigs from the second backcross (BC 2 ) generation in a family material originating from two wild boar x Large White intercrosses. Also, MBL-A serum concentration was measured in the entire BC 2 generation (n = 45). Furthermore, the genotypes of 68 wild boars from Sweden, Austria, the Czech Republic, and Japan were determined in regard to five previously described SNPs in MBL1 . The T allele of G949T was present among the BC 2 animals. MBL-A serum concentration in the BC 2 animals showed a bimodal distribution, with one-third of the animals at levels between 0.7 and 1.6 µg mL(-1) and the remaining pigs at levels around 13 µg mL(-1) . There was a co-variation between the presence of the T allele and low MBL-A concentration in serum. The genotyping of the wild boars revealed differences between populations. The T allele of G949T was not detected in the Austrian and Japanese samples and is thus unlikely to be an original feature of wild boars. In contrast, it was present at high frequency (0.35) among the Swedish wild boars, probably representing a founder effect. Five MBL1 haplotypes were resolved. Only two of these were present among the Japanese wild boars compared to four in each of the European populations. This difference may reflect differences in selection pressure and population history.


Subject(s)
Mannose-Binding Lectin/blood , Mannose-Binding Lectin/genetics , Sus scrofa/genetics , Animals , Austria , Base Sequence , Czech Republic , Gene Frequency , Genotype , Haplotypes , Japan , Polymorphism, Single Nucleotide , Receptors, Pattern Recognition/genetics , Sequence Analysis, DNA/veterinary , Sweden
5.
Cancer Gene Ther ; 19(4): 282-91, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22240921

ABSTRACT

A generally applicable, easy-to-use method of focusing a patient's immune system to eradicate or prevent cancer has been elusive. We are attempting to develop a targeted virus to accomplish these aims. We previously created a recombinant replicating vesicular stomatitis virus (VSV) that preferentially infected Her2/neu expressing breast cancer cells and showed therapeutic efficacy in an implanted Balb/c mouse tumor model. The current work shows that this therapy generated therapeutic anti-tumor CD4 T cells against multiple tumor antigens. CD4 T cells transferred directly from cured donor mice could eradicate established tumors in host mice. T cells were transferred directly from donor mice and were not stimulated ex vivo. Both tumors that expressed Her2/neu and those that did not were cured by transferred T cells. Analysis of cytokines secreted by anti-tumor memory CD4 T cells displayed a multifunctional pattern with high levels of interferon-γ, interleukin (IL)-4 and IL-17. Anti-tumor memory CD4 T cells traveled to the mesenteric lymph nodes and were activated there. Treatment with targeted recombinant replicating VSV is a potent immune adjuvant that generates therapeutic, multifunctional anti-tumor memory CD4 T cells that recognize multiple tumor antigens. Immunity elicited by viral therapy is independent of host major histocompatibility complex or knowledge of tumor antigens. Virus-induced tumor immunity could have great benefit in the prevention and treatment of tumor metastases.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Genetic Vectors/genetics , Immunologic Memory/immunology , Neoplasms/genetics , Neoplasms/immunology , Vesicular stomatitis Indiana virus/genetics , Adoptive Transfer , Animals , B-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Cell Line , Cytokines/biosynthesis , Female , Genetic Vectors/administration & dosage , Genetic Vectors/immunology , Humans , Mice , Mice, Inbred BALB C , Neoplasms/mortality , Neoplasms/therapy , Vesicular stomatitis Indiana virus/immunology
6.
Int J Immunogenet ; 39(1): 68-76, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22077964

ABSTRACT

The great importance of the Toll-like receptors (TLRs) in innate immunity is well established, but one family member--TLR10--remains elusive. TLR10 is expressed in various tissues in several species, but its ligand is not known and its function is still poorly understood. The open reading frame of TLR10 was sequenced in 15 wild boars, representing three populations, and in 15 unrelated domestic pigs of Hampshire, Landrace and Large White origin. Amino acid positions corresponding to detected nonsynonymous single nucleotide polymorphisms (SNPs) were analysed in the crystal structures determined for the human TLR1-TLR2-lipopeptide complex and the human TLR10 Toll/Interleukin 1 receptor (TIR) dimer. SNP occurrence in wild boars and domestic pigs was compared, and haplotypes for the TLR10 gene and the TLR6-1-10 gene cluster were reconstructed. Despite the limited number of animals sequenced in the present study (N = 30), a larger number of SNPs were found in TLR10 than recently reported for TLR1, TLR6 and TLR2. Thirty-three SNPs were detected, of which 20 were nonsynonymous. The relative frequency of nonsynonymous (d(N) ) and synonymous (d(S) ) SNPs between wild boars and domestic pigs was higher in TLR10 than recently reported for TLR1, TLR6 and TLR2. However, the polymorphism reported in the present study seems to leave the function of the TLR10 molecule unaffected. Furthermore, no nonsynonymous SNPs were detected in the part of the gene corresponding to the hinge region of the receptor, probably reflecting rigorously acting functional constraint. The total number of SNPs and the number of nonsynonymous SNPs were significantly lower (P < 0.05) in the wild boars than in the domestic pigs, and fewer TLR10 haplotypes were present in the wild boars. The majority of the TLR6-1-10 haplotypes were specific for either wild boars or domestic pigs, probably reflecting differences in microbial environment and population history.


Subject(s)
Polymorphism, Single Nucleotide , Swine/genetics , Toll-Like Receptor 10/genetics , Animals , Binding Sites , Female , Gene Frequency , Genetic Carrier Screening , Haplotypes , Male , Open Reading Frames , Phylogeny , Protein Structure, Tertiary , Sequence Alignment , Species Specificity , Swine/classification , Swine/immunology , Toll-Like Receptor 1/genetics , Toll-Like Receptor 2/genetics , Toll-Like Receptor 6/genetics
7.
Cancer Gene Ther ; 16(1): 44-52, 2009 Jan.
Article in English | MEDLINE | ID: mdl-18654610

ABSTRACT

Vesicular stomatitis virus (VSV) is being developed for cancer therapy. We created a recombinant replicating VSV (rrVSV) that preferentially infected Her2/neu expressing breast cancer cells. We now used this rrVSV to treat macroscopic peritoneal tumor implants of a mouse mammary tumor cell line stably transfected to express Her2/neu. rrVSV therapy alone prolonged survival but did not cure any animals. rrVSV therapy combined with antibody to TGFb or antibody to IL-10 receptor (IL-10R) each produced cure in one of six animals. Strikingly, rrVSV therapy combined with anti-CTLA4 monoclonal antibody (MAb) produced cure in four of five animals. Anti-CTLA4 MAb was only effective when administered within one day of rrVSV therapy. Cure required CD4 T-cells early (<7 days) and late (>7 days) after rrVSV therapy whereas CD8 T-cells were required only late (>7 days) after rrVSV therapy. Surviving animals were resistant to re-challenge with D2F2/E2 suggesting a memory immune response. Histopathologic analysis demonstrated a dense inflammatory infiltrate of tumor nodules within days of therapy and foamy histiocytes replacing the tumor nodules 2 weeks following therapy. These studies demonstrate that targeted rrVSV combined with anti-CTLA4 MAb can eliminate established macroscopic tumor implants by eliciting an anti-tumor CD4 and CD8 T-cell immunologic response.


Subject(s)
Antibodies, Monoclonal/pharmacology , Antigens, CD/immunology , Immunologic Memory , Mammary Neoplasms, Experimental/therapy , Receptor, ErbB-2/immunology , Vesiculovirus , Animals , Antibodies, Monoclonal/immunology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/pathology , CTLA-4 Antigen , Cell Line, Tumor , Female , Gene Expression Regulation, Neoplastic/genetics , Gene Expression Regulation, Neoplastic/immunology , Humans , Immunologic Memory/drug effects , Inflammation/genetics , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Mammary Neoplasms, Experimental/genetics , Mammary Neoplasms, Experimental/immunology , Mammary Neoplasms, Experimental/metabolism , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Inbred BALB C , Receptor, ErbB-2/biosynthesis , Time Factors , Transfection
8.
Anaesth Intensive Care ; 35(1): 140-1; author reply 141-2, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17323685
9.
Anaesthesia ; 60(3): 220-7, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15710005

ABSTRACT

Eight hundred and ninety-six incidents relating to drug error were reported to the Australian Incident Monitoring Study. Syringe and drug preparation errors accounted for 452 (50.4%) incidents, including 169 (18.9%) involving syringe swaps where the drug was correctly labelled but given in error, and 187 (20.8%) due to selection of the wrong ampoule or drug labelling errors. The drugs most commonly involved were neuromuscular blocking agents, followed by opioids. Equipment misuse or malfunction accounted for a further 234 (26.1%) incidents; incorrect route of administration 126 (14.1%) incidents; and communication error 35 (3.9%) incidents. The outcomes of these events included minor morbidity in 105 (11.7%), major morbidity in 42 (4.7%), death in three (0.3%) and awareness under anaesthesia in 40 (4.4%) incidents. Contributing factors included inattention, haste, drug labelling error, communication failure and fatigue. Factors minimising the events were prior experience and training, rechecking equipment and monitors capable of detecting the incident. The information gained suggests areas where improved guidelines are required to reduce the incidence of drug error. Further research is required into the effectiveness of preventive strategies.


Subject(s)
Anesthesia/standards , Medication Errors/statistics & numerical data , Adolescent , Adult , Anesthesia/adverse effects , Australia , Child , Child, Preschool , Clinical Competence , Communication , Databases as Topic , Drug Labeling/standards , Equipment Failure , Humans , Infant , Infant, Newborn , Medication Errors/prevention & control , Risk Factors , Risk Management , Syringes
11.
Anaesthesia ; 57(6): 549-56, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12010269

ABSTRACT

Because of recent studies suggesting that awareness is still a major issue in anaesthetic practice, we reviewed 8372 incidents reported to the Anaesthetic Incident Monitoring Study. There were 81 cases in which peri-operative recall was consistent with awareness. There were 50 cases of definite awareness and 31 cases with a high probability of awareness. In 13 of the 81 incidents, the patients appeared to receive adequate doses of anaesthetic drugs. Where the cause could be determined, awareness was mainly due to drug error resulting in inadvertent paralysis of an awake patient (n = 32) and failure of delivery of volatile anaesthetic (n = 16). Less common causes included prolonged attempts at intubation of the trachea (n = 5), deliberate withdrawal of volatile anaesthetic (n = 4) or muscle relaxant apnoea with inadequate administration of hypnotic (n = 3). An objective central nervous system depth of anaesthesia monitor may have prevented 42 of these incidents and an improved drug administration system may have prevented 32. On the basis of these reports, we have developed guidelines that may have prevented the majority of these incidents.


Subject(s)
Anesthesia, General , Awareness , Anesthetics/administration & dosage , Equipment Failure , Humans , Medical Errors , Paralysis/chemically induced
12.
Med Sci Monit ; 7(5): 977-81, 2001.
Article in English | MEDLINE | ID: mdl-11535945

ABSTRACT

BACKGROUND: The pathogenesis of mumps meningitis remains unclear. The aim of this study was to assess the relation between IgM and IgG levels in blood and their relationship with the picture of CSF. MATERIAL AND METHODS: We tested 40 children of both sexes aged 2-14 years. CSF was examined at admission (I) and after 12-14 days (II). Antibodies were measured four times: at admission (I), and after 2 (II), 4 (III), and 8 weeks (IV) by EIA (Behring). The results were expressed as delta absorbency. RESULTS: The mean IgM level was respectively 0.403; 0.424; 0.317; 0.220. Significant differences were demonstrated between tests I and III and between III and IV. The mean IgG level was respectively 0.923; 1.322; 1.381 and 1.257. Significant differences were noted between tests I and II and between III and IV. We observed significant positive correlations between the IgM levels in tests I and II, II and III, and III and IV. The IgG concentrations significantly correlated in tests I and II, II and III, and II and IV. Significant negative correlations were noted between the IgG levels at test I and the IgM levels at test II. A negative correlation also appeared between the IgM level and CFS pleocytosis at admission, and between the IgM concentration and CSF pleocytosis after two weeks. A positive correlation was found between the IgG level at test I and the CSF glucose level in test II. In this study a high IgG level probably resulted in a lower IgM level at the next test. The IgM concentration at week 8 weeks was about 50% lower than its highest concentration (week 2), while the IgG level decreased simultaneously. The IgM concentration at hospital admission and two weeks later influenced CSF pleocytosis during these periods (higher IgM level - lower pleocytosis). A high IgG level at admission resulted in a lower CSF glucose concentration at the second examination.


Subject(s)
Immunoglobulin G/blood , Immunoglobulin M/blood , Meningitis, Viral/immunology , Mumps virus/immunology , Mumps/immunology , Adolescent , Antibodies, Viral/blood , Cerebrospinal Fluid/chemistry , Child , Child, Preschool , Humans , Meningitis, Viral/cerebrospinal fluid , Mumps/cerebrospinal fluid , Mumps/complications , Statistics as Topic
13.
Clin Cancer Res ; 7(7): 2050-6, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11448923

ABSTRACT

The metastatic spread of breast cancer to the leptomeninges (LM) is a painful, debilitating, and usually lethal condition. Current therapies are generally ineffective or extremely toxic. The current study evaluated monoclonal antibody therapy in an animal model of LM human breast cancer. Monoclonal antibody 4D5, which recognizes the extracellular domain of the HER2/neu receptor, was administered into the cerebrospinal fluid of athymic rats implanted with human breast cancer cell lines. Continuous intraventricular administration of 4D5 inhibited growth of SKBR3 cells that overexpress HER2/neu but not of MCF7 cells, which do not. Inhibition was dose-dependent, with higher doses of 4D5 producing an improved response. i.p. administration of cisplatin in addition to 4D5 did not improve results. Continuous administration of 4D5 into the lumbar, as opposed to the ventricular intrathecal space, was not therapeutically effective. Treatment with 4D5 did not result in outgrowth of cells lacking expression of the HER2/neu receptor. These results suggest that 4D5, administered regionally, may palliate LM metastases from HER2/neu-overexpressing breast carcinoma.


Subject(s)
Antibodies, Monoclonal/pharmacology , Breast Neoplasms/drug therapy , Meningeal Neoplasms/drug therapy , Receptor, ErbB-2/immunology , Animals , Antibodies, Monoclonal/cerebrospinal fluid , Antibodies, Monoclonal/therapeutic use , Brain/drug effects , Brain/immunology , Brain/pathology , Breast Neoplasms/immunology , Breast Neoplasms/pathology , Cell Division/drug effects , Dose-Response Relationship, Drug , Female , Humans , Immunohistochemistry , Injections, Intraventricular , Meningeal Neoplasms/secondary , Neoplasm Transplantation , Rats , Rats, Nude , Receptor, ErbB-2/metabolism , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
14.
FEMS Microbiol Ecol ; 33(3): 181-189, 2000 Sep 01.
Article in English | MEDLINE | ID: mdl-11098069

ABSTRACT

The methane produced in peat soils can vary over the growing season due to variations in the supply of available substrate, the activity of the microbial community or changes in temperature. Our aim was to study how these factors regulate the methane production over the season from five different peat types of different botanical origin. Peat samples were collected on seven occasions between June and September. After each sampling, the peat soils were incubated at five different temperatures (7, 10, 15, 20 and 25 degrees C) without added substrate, or at 20 degrees C with added substrate (glucose, or H(2)/CO(2), or starch). Rates of methane production averaged over the season differed significantly (P<0.05, R(2)=0.76) among the five peat types, the minerotrophic lawn producing the highest rates, and the hummock peat producing the lowest. The seasonal average Q(10) values for each plant community varied between 4.6 and 9.2, the highest value being associated with the ombrotrophic lawn and the lowest value with the mud-bottom plant community. For the unamended peat samples, the rates of methane production from each plant community varied significantly (P<0.05) over the season. This implies that the quality of organic matter, in combination with changes in temperature, explains the seasonal variation in methane production. However, addition of saturating amounts of glucose, H(2)/CO(2) or starch at 20 degrees C significantly reduced the seasonal variation (P<0.05) in methane production in peat from the minerotrophic lawn, wet carpet and mud-bottom plant communities. This suggests that substrate supply (e.g. root exudates) for the micro-organisms also varied over the season at these sites. Seasonal variation in methane production rates was apparent in peat from the hummock and ombrotrophic lawn plant communities even after addition of substrates, suggesting that the active biomass of the anaerobic microbial populations at these sites was regulated by other factors than the ones studied.

15.
Cancer Immunol Immunother ; 49(4-5): 259-66, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10941909

ABSTRACT

Antibodies can direct tumor cell lysis by activating complement-mediated and cell-mediated cytoxicities (antibody-dependent cell-mediated cytotoxicity, ADCC). Clinical translation of these effects into successful cancer therapy has been slow. Choosing an appropriate animal model to test new therapeutic strategies is difficult because of species differences in immunological effector functions. In previous work, we found that an unmodified anti-ganglioside mouse IgG3 monoclonal antibody (mAb), 3F8, could successfully treat clinical tumors in humans and experimental tumors in rats but not experimental tumors in mice. We explored the reasons for this species difference by performing in vitro antibody-dependent cytotoxicity assays comparing the potency of polymorphonuclear neutrophils (PMN), natural killer (NK) cells and complement from the three species: mouse, rat and human. 3F8-dependent complement-mediated cytotoxicity produced more than 70% specific release when human and rat sera were used and only 20% with mouse serum. PMN-mediated ADCC was 35%-70% with human effectors, 25%-60% with rat and undetectable with mouse. Human eosinophils did not contribute to this ADCC. Cytotoxicity utilizing interleukin-2-activated NK cells was antibody-independent in all three species but the specific release was 60%-70% with human and rat NK cells and 10% with mouse NK cells. These data suggest that, for mouse IgG3, the rat may provide a more relevant rodent model than the mouse for testing the in vivo antitumor effects of monoclonal antibodies.


Subject(s)
Antibody-Dependent Cell Cytotoxicity , Complement System Proteins/immunology , Eosinophils/immunology , Killer Cells, Natural/immunology , Neutrophils/immunology , Animals , Antibodies, Monoclonal/immunology , Chromium/pharmacokinetics , Dose-Response Relationship, Immunologic , Humans , Immunoglobulin G/immunology , Interleukin-2/metabolism , Mice , Mice, Inbred BALB C , Rats , Species Specificity , Tumor Cells, Cultured
16.
Int J Cancer ; 82(4): 538-48, 1999 Aug 12.
Article in English | MEDLINE | ID: mdl-10404068

ABSTRACT

Leptomeningeal (LM) neoplastic metastases are painful, debilitating and inevitably lethal. Intrathecal (IT) anti-tumor antibodies may have therapeutic potential. We evaluated 3F8, an anti-G(D2) murine IgG(3) monoclonal antibody (MAb) in the treatment of human melanoma (SKMEL-1) and neuroblastoma (NMB7) xenografts in athymic rats. Both tumors were lysed efficiently in vitro by 3F8 in the presence of rat neutrophils or rat complement. Antibody-dependent cellular cytotoxicity (ADCC) was not augmented by recombinant human GM-CSF (rhGM-CSF), rhG-CSF, recombinant rat MIP-2 (rrMIP-2) or lipopolysaccharide (LPS). In vivo, continuous intraventricular administration of 3F8 and LPS prevented tumor engraftment, retarded tumor growth and eradicated 3-day-old established xenografts whereas 3F8 alone, LPS alone or F(ab)'(2) plus LPS had no or only marginal effects. Tumor establishment in brain was completely prevented in 36% of animals implanted with SKMEL-1 and 65% of animals implanted with NMB7. Twenty percent of established xenografts around the brain were eradicated but all animals had persistent tumor in the lumbosacral meninges despite treatment. Continuous intraventricular infusion of LPS produced a variable polymorphonuclear (PMN) pleocytosis that was dose-dependent. Continuous intraventricular infusion of 3F8 produced immunohistochemically detectable attachment to 86% of persistent brain deposits of tumor but <1% of spinal lumbosacral deposits. We conclude that regional therapy with anti-G(D2) MAb could target neutrophils to inhibit LM tumor growth. However, optimal activation and mobilization of neutrophils into the cerebrospinal fluid (CSF) and improved penetration of MAb to tumor sites remain critical variables.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Chondroitin Sulfate Proteoglycans/immunology , Gangliosides/immunology , Immunotherapy/methods , Lipopolysaccharides/administration & dosage , Melanoma/prevention & control , Meningeal Neoplasms/prevention & control , Neuroblastoma/prevention & control , Animals , Antibodies, Monoclonal/cerebrospinal fluid , Female , Humans , Injections, Intraventricular , Melanoma/cerebrospinal fluid , Melanoma/secondary , Meningeal Neoplasms/cerebrospinal fluid , Meningeal Neoplasms/secondary , Neuroblastoma/cerebrospinal fluid , Neuroblastoma/secondary , Rats , Rats, Nude , Receptor-Like Protein Tyrosine Phosphatases, Class 5 , Transplantation, Heterologous
17.
J Immunother ; 22(2): 114-23, 1999 Mar.
Article in English | MEDLINE | ID: mdl-10093036

ABSTRACT

Intrathecal (i.t.) administration of monoclonal antibodies (MAbs) represents a new therapeutic approach for the treatment of leptomeningeal (LM) cancer, which is presently rapidly fatal. In this study, we quantitated the accumulation of an intrathecally administered anti-ganglioside GD2 MAb (3F8) within leptomeningeal neoplastic xenografts of GD2 positive melanoma and neuroblastoma in nude rats by measuring concentrations of radiolabeled and unmodified MAbs and by immunohistochemistry. Intrathecal administration of 125I-3F8 resulted in area under the tissue concentration versus time curve (AUC) values in SK-MEL-1 melanoma xenografts (53.1 microCi*h/g) that were 14-fold greater than in corresponding blood (3.9 microCi*h/g), whereas i.t. administration of a control nonspecific MAb resulted in AUC values in tumors (7.1 microCi*h/g) that were less than those in blood (9.5 microCi*h/g). Administration of acetazolamide and furosemide, which slow the clearance of IgG MAb from rat cerebrospinal fluid resulted in a fivefold increase in AUC of 125I-3F8 in melanoma (262.9 microCi*h/g). The highest concentration of 125I-MAb in tumor after i.t. administration was seen at the first sampling time of 2 h, and this fell to 50% of maximum values at 8-16 h. Pharmacokinetic analysis of unmodified MAb demonstrated retention of MAb within the LM space of animals with tumor. The concentration of MAb 3F8 appearing in serum after i.t. administration was 10-fold lower in animals with melanoma xenografts than in those without tumor implants. Radiation dose estimates after intraventricular administration of radiolabeled MAb indicated delivery to tumor of 1,870 rad/mCi of 125I-3F8 but only 40 rad/mCi of 125I-labeled control MAb. These results indicate that anti-ganglioside MAbs and other MAbs directed to tumor-associated antigens are excellent candidates for i.t. treatment of appropriate leptomeningeal cancers in humans.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Gangliosides/immunology , Meningeal Neoplasms/therapy , Acetazolamide/pharmacology , Animals , Antibodies, Monoclonal/pharmacokinetics , Female , Furosemide/pharmacology , Immunohistochemistry , Injections, Spinal , Iodine Radioisotopes , Meningeal Neoplasms/metabolism , Neoplasm Transplantation , Radiation Dosage , Rats , Tissue Distribution , Transplantation, Heterologous
18.
Scand J Psychol ; 39(1): 47-54, 1998 Mar.
Article in English | MEDLINE | ID: mdl-9619132

ABSTRACT

This study identifies personality characteristics in a group of Swedish women (N = 60) attending their first treatment for alcohol problems. The treatment programme specifically addressed women in an early phase of their drinking career, and was called "Early Treatment of Women with Alcohol Addiction" (EWA). Rorschach personality profiles of the 60 women differed significantly in almost all investigated aspects in a psychopathological direction from norms reported by Exner for a reference group of female non-patients. The findings are consistent with the assumption that, although the EWA women were socially well-functioning and fairly early in their drinking career, they nevertheless reveal serious underlying psychopathology. Clinical implications of the findings are discussed.


Subject(s)
Alcoholism/psychology , Personality , Adult , Aged , Alcoholism/complications , Female , Humans , Mental Disorders/complications , Middle Aged , Rorschach Test , Self Concept , Social Perception , Sweden
19.
Pediatr Neurol ; 18(4): 299-304, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9588523

ABSTRACT

Mortality is high in patients with fulminant hepatic failure (FHF). Neurologic complications of encephalopathy and cerebral edema are major contributors to mortality. Orthotopic liver transplantation has improved survival in these patients. However, the complexity of medical and surgical problems in this patient population, coupled with a severe shortage of organs, requires careful patient selection. The aim of this study was to describe the neurologic outcome of children with FHF who developed radiologically apparent cerebral edema. The hospital and outpatient records and radiologic studies of 20 children with FHF admitted to Children's Hospital of Pittsburgh from 1981-1995 who developed encephalopathy and computed tomographic evidence of cerebral edema were reviewed. Fourteen patients died (70%), three were left with severe neurologic deficits (15%), and three were left with moderate deficits (15%). Survival was correlated with a lesser degree of coma. Histopathologic examination of eight brains demonstrated cerebral edema and widespread ischemic neuronal necrosis in all eight. The presence of radiographic cerebral edema in children with FHF is an objective measure that indicates a very poor prognosis. Termination of care is a reasonable option. Comprehensive monitoring of cerebral function and intracranial pressure is required in children with FHF. Orthotopic liver transplantation should be performed in children with severe and worsening encephalopathy before the development of radiographically apparent cerebral edema.


Subject(s)
Brain Edema/therapy , Hepatic Encephalopathy/complications , Adolescent , Brain Damage, Chronic/epidemiology , Brain Damage, Chronic/etiology , Brain Edema/diagnostic imaging , Brain Edema/etiology , Brain Edema/mortality , Brain Edema/pathology , Brain Ischemia/etiology , Brain Ischemia/pathology , Child , Child, Preschool , Female , Follow-Up Studies , Hepatic Encephalopathy/mortality , Humans , Infant , Intracranial Pressure , Liver Transplantation , Male , Necrosis , Neurons/pathology , Pennsylvania/epidemiology , Predictive Value of Tests , Severity of Illness Index , Single-Blind Method , Survival Analysis , Tomography, X-Ray Computed , Treatment Outcome
20.
J Pharmacol Exp Ther ; 284(1): 111-5, 1998 Jan.
Article in English | MEDLINE | ID: mdl-9435168

ABSTRACT

Intrathecal (i.t.) administration of monoclonal antibodies (mAbs) represents a new therapeutic approach for the treatment of leptomeningeal cancer, which is rapidly fatal. This study describes the pharmacokinetics of intrathecally administered mAbs in rats and monkeys to optimize their use for regional antineoplastic therapy. We hypothesized that mAbs, which are high-molecular-weight, polar compounds, would be eliminated from the cerebrospinal fluid (CSF) at the same rate as bulk flow of CSF. We found that an IgM mAb was cleared from rat CSF at the rate of CSF bulk flow (0.0041 ml/min), but an IgG mAb was cleared at a faster rate (0.011 ml/min). We attempted to reduce the CSF clearance of an IgG mAb by administration of acetazolamide and furosemide, which inhibit the rate of CSF production and CSF bulk flow. We demonstrated that the administration of acetazolamide and furosemide reduced the clearance of IgG mAb from rat CSF by 58%. These results establish that bulk flow of CSF determines a minimum rate of elimination from the CSF for IgM mAbs and that additional mechanisms operate to clear IgG mAbs from the CSF. Inhibition of CSF production by acetazolamide and furosemide increased the area under the CSF concentration vs. time curve of IgG mAbs in the CSF. The increased area under the CSF concentration vs. time curve is likely to improve the therapeutic index of these agents for i.t. therapy.


Subject(s)
Antibodies, Monoclonal/pharmacokinetics , Gangliosides/immunology , Immunoglobulin G/metabolism , Immunoglobulin M/metabolism , Animals , Antibodies, Monoclonal/administration & dosage , Female , Injections, Intravenous , Injections, Spinal , Macaca mulatta , Male , Rats
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