Biomedical subjects

M L Casal

Publications and source records attributed to M L Casal.

13 recordsLinked to original sources

PubMed2004

Familial glomerulonephropathy in the Bullmastiff.

Glomerular disease was diagnosed by histopathologic examination in 11 related Bullmastiff dogs, and clinical and laboratory data were collected retrospectively. Four female and seven male dogs between the ages of 2.5 and 11 years were affected. Clinical signs, including lethargy and anorexia, were nonspecific and occurred shortly before death or euthanasia. In five affected dogs serial blood samples were obtained, and dramatically elevated blood urea nitrogen and creatinine levels were demonstrated up to 2.75 years before death. Protein-creatinine ratios were elevated in six of six dogs and were above normal 3.5 years before death in one dog. The kidneys appeared grossly normal to slightly smaller than normal at necropsy. Histologic abnormalities of the kidneys were consistent with chronic glomerulonephropathy with sclerosis. Examination of the pedigrees of related affected dogs yielded evidence supporting an autosomal recessive mode of inheritance.

Animals↗

PubMed2001

In utero transplantation of fetal liver cells in the mucopolysaccharidosis type VII mouse results in low-level chimerism, but overexpression of beta-glucuronidase can delay onset of clinical signs.

Mice with the lysosomal storage disease mucopolysaccharidosis (MPS) VII, caused by a deficiency of beta-glucuronidase (GUSB), have signs of disease present at birth. Bone marrow transplantation (BMT) or retroviral vector-mediated gene transfer into hematopoietic stem cells can partially correct the disease in adult mice, and BMT performed at birth results in a better clinical outcome. Thus, treatment in utero may result in further improvement. However, this must be done without cyto-ablation, and the donor cells do not have a competitive repopulating advantage over host cells. Transplantation in utero of either syngeneic fetal liver hematopoietic stem cells marked with a retroviral vector, or allogeneic donor cells that constitutively express high levels of human GUSB from a transgene, resulted in only about 0.1% engraftment in the adult. Immuno-affinity enrichment of stem and progenitor cells of 5- to 10-fold resulted in significantly higher GUSB activities at 2 months of age, but by 6 months engraftment was about 0.1%. Attempts to further increase the number of stem and progenitor cells were deleterious to the recipients. Nevertheless, GUSB expressed during the first 2 months of life in MPS VII fetuses could delay the onset of overt signs of disease. This suggests that the expression of some normal enzyme activity beginning in fetal life may offer the possibility of slowing the progression of the disease until more definitive postnatal transplantation or gene transfer to stem cells could be accomplished.

Animals↗

PubMed2000

Canine cystinuria: polymorphism in the canine SLC3A1 gene and identification of a nonsense mutation in cystinuric Newfoundland dogs.

Cystinuria is an inherited renal and intestinal disease characterized by defective amino acid reabsorption and cystine urolithiasis. Different forms of the disease, designated type I and non-type I in cystinuric humans, can be distinguished clinically and biochemically, and have been associated with mutations in the SLC3A1 (rBAT) and SLC7A9 genes, respectively. Type I cystinuria is the most common form and is inherited as an autosomal recessive trait in humans. Cystinuria has been recognized in more than 60 breeds of dogs and a severe form, resembling type I cystinuria, has been characterized in the Newfoundland breed. Here we report the cloning and sequencing of the canine SLC3A1 cDNA and gene, and the identification of a nonsense mutation in exon 2 of the gene in cystinuric Newfoundland dogs. A mutation-specific test was developed for the diagnosis and control of cystinuria in Newfoundland dogs. In cystinuric dogs of six other breeds, either heterozygosity at the SLC3A1 locus or lack of mutations in the coding region of the SLC3A1 gene were observed, indicating that cystinuria is genetically heterogeneous in dogs, as it is in humans. The canine homologue of human type I cystinuria provides the opportunity to use a large animal model to investigate molecular approaches for the treatment of cystinuria and other renal tubular diseases.

Amino Acid Sequence↗

PubMed2000

Effects of bone marrow transplantation on the cardiovascular abnormalities in canine mucopolysaccharidosis VII.

The genetic mucopolysaccharidoses (MPS) are a family of lysosomal storage diseases resulting from defective catabolism of glycosaminoglycans (GAGs). Echocardiographic abnormalities in dogs with MPS type VII (Sly syndrome, beta-glucuronidase deficiency) included mitral valve thickening and insufficiency, large aortic dimensions in both the long and short axes, and thickened aortic valves. Grossly, at post mortem examination, there was nodular thickening of the mitral valve, a prominent ductus diverticulum, and a dilated aorta with thickened walls. Histologically, cytoplasmic vacuolation was seen in cells of the mitral valves, coronary arteries, and aorta. By electron microscopy, the cells of the mitral valve were packed with electron-lucent cytoplasmic vacuoles. The mean residual activity of beta-glucuronidase in the aorta and myocardium was <1% of normal, the mean hexosaminidase A activity >2. 5 times normal, and the mean GAG concentrations more than twice normal. In three MPS VII dogs that received heterologous BMT at 6 weeks of age, the echocardiographic abnormalities were improved, and the histopathologic and ultrastructural pathology was reduced. In the aorta and myocardium, the mean beta-glucuronidase activity of the BMT group was 4.5% and 11% of normal, respectively, and the hexosaminidase A activity and GAG concentrations were normalized. Bone Marrow Transplantation (2000) 25, 1289-1297.

Animals↗

PubMed2000

Mucopolysaccharidosis type VII in the developing mouse fetus.

Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by a deficiency of beta-glucuronidase (1). MPS VII is a fatal, progressive degenerative disorder, and a number of patients die of hydrops fetalis. Thus an approach to treating this disease may be by transplantation or gene therapy in utero. A mouse model of MPS VII has been studied extensively but the disease in affected fetal mice has not been characterized, which is essential for evaluation of therapeutic efficacy. Fetal and newborn mice affected with MPS VII were examined for lysosomal enzyme activities and for the presence of typical storage lesions in comparison to normal and carrier littermates. No beta-glucuronidase enzymatic activity was detected in any of the tissues of affected mice, indicating that transplacental transfer of beta-glucuronidase from the dam did not occur. Lesions were not detected in affected fetuses of 13.5 d gestational age on light or electron microscopy. Vacuolation in cells, typical of lysosomal accumulation of substrate, was first seen in a small number of cells of the reticulo-endothelial system in 15.5 d gestational age livers and in 18.5 d gestational age brains. Storage lesions were not seen consistently in endothelial and Kupffer cells of fetal livers until 18.5 d gestational age and in brains until birth. The results suggest that treatment of affected mice performed at 13.5 d gestational age may be effective in forestalling disease manifestations.

Animals↗

PubMed1998

Variant clinical course of mucopolysaccharidosis type VII in two groups of mice carrying the same mutation.

Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by a deficiency in beta-glucuronidase. The disease has been well-characterized in B6.C-H-2bml/ByBir-gus(mps/mps) mice, which have proven to be an excellent model for the study of treatment modalities of storage diseases. However, because of the progressive nature of the disease, the mice deteriorate rapidly, have a greatly decreased life span, and are infertile. To increase fitness, B6.C-H-2bml/ByBir-gus(mps/+) were interbred with normal C3H mice. This study compares clinical findings, fertility, longevity, and gross and microscopic findings in the original strain with those in the F2 generation of the interbred strain.

Animals↗

PubMed1997

Amphotropic and ecotropic retroviral vector viruses transduce midgestational murine fetal liver cells in a dual-chambered cocultivation system.

A beta-glucuronidase cDNA was transferred into fetal liver cells (FLC) from mice affected with mucopolysaccharidosis (MPS) type VII and normal littermates using a retrovirus vector. The cells were transduced by direct cocultivation or by culturing the FLC and vector packaging cells separated by a 0.45 micron filter in a dual-chambered cocultivation system. Gene transduction occurred using an ecotropic or amphotropic vector in FLC obtained from 13.5- and 15.5-day-old murine fetuses. Histochemical staining assays and measurement of enzyme activity demonstrated gene expression in the midgestational FLC. Enzyme secreted into the supernatant from transduced FLC obtained from 13.5-day-old affected fetuses surpassed secreted enzyme from normal, age-matched untransduced FLC. The 13.5 day FLC, transduced by direct cocultivation or by using the dual-chambered system, were transplanted in utero into 13.5-day-old murine fetuses. Proviral sequences were detected in various organs shortly after birth. The results indicate that midgestational FLC can be transduced with an amphotropic vector virus in a dual-chambered cocultivation system without contaminating virus-producing packaging cells and that the transduced cells survive in utero transplantation.

Animals↗

PubMed1997

Feline colostrum--friend or foe: maternal antibodies in queens and kittens.

The transfer of immunoglobulins (Ig) by colostrum from the queen to the neonatal kitten not only provides protection from infection, but may also cause serious illness. Neonatal isoerythrolysis may occur when kittens of blood type A or AB receive colostral anti-A alloantibodies from a type B queen. In contrast to other species, Ig concentrations in milk and colostrum did not differ markedly. Gastrointestinal absorption of IgG was limited to the first day of life. The half-lifes of maternally derived IgG and IgA in kittens were shorter than in puppies. In conclusion, milk from another queen may be given as a replacement for colostrum to neonatal kittens. Kittens at risk of neonatal isoerythrolysis must be removed from their type B queen during the first day of life and may safely receive milk or colostrum from a type A queen.

ABO Blood-Group System↗

PubMed1996

Blood type AB in the feline AB blood group system.

OBJECTIVE: To assess the genetics, frequency, and biochemistry of the AB blood type in cats. ANIMALS: Domestic shorthair and purebred cats in a breeding colony and privately owned catteries and blood samples from a large feline blood typing laboratory. PROCEDURES: Samples from cats with blood type AB were selected from the feline blood typing laboratory at the university. Breeding experiments and family studies were used for the genetic analysis of cats with blood type AB. Simple slide hemagglutination assays were used to type cats. Hemagglutination assays, flow cytometry, and ganglioside analysis by high-performance thin layer chromatography were applied to characterize the AB antigens. RESULTS: Type AB was rare (13/9,239 cats; 0.14% frequency) in cats of the United States and Canada. Type AB occurred only in breeds in which type B was also detected. Cats with type-AB blood express biochemical features of type-A and type-B antigens. Genetic analyses of families with blood type-AB cats are consistent with the hypothesis of 3 alleles: A, B, and AB. The AB allele is recessive to the A allele, but dominant over the B allele. There may be an additional genetic mechanism responsible for the inheritance of blood type AB in cats. CONCLUSION: Blood type AE is an extremely rare and separately inherited type in the feline AB blood group system. CLINICAL RELEVANCE: Kittens with type-AB blood born to queens with type-B blood are at similar risk for neonatal isoerythrolysis as kittens with type-A blood because anti-A alloantiserum from blood type-B queens recognizes AB red blood cells. Furthermore, cats with type-AB blood are best transfused with type-AB or type-A blood.

ABO Blood-Group System↗

PubMed1996

Transfer of colostral antibodies from queens to their kittens.

OBJECTIVE: To examine systemic immunity in kittens, including transfer of maternal immunoglobulins from the queen to kittens, and subsequent decay of passively obtained immunoglobulins. ANIMALS: 6 healthy queens and their 46 kittens. PROCEDURE: Immunoglobulin concentrations were measured in serum, colostrum, and milk of queens and in their kittens' sera. Decay rate constants and half-lives of maternally derived immunoglobulins were determined. To determine intestinal absorption, foreign IgG was given to kittens at 6- to 8-hour intervals after birth, and bovine IgM was given to kittens at birth. RESULTS: Immunoglobulin concentrations of milk and colostrum did not differ significantly after removal of milk fat. Mean IgG concentration was higher in colostrum/ milk, whereas mean IgA and IgM concentrations were lower than those in the queens' serum. No IgG or IgA was detected in any of the precolostral serum samples obtained from kittens. Small amounts of IgM were present in the sera from 5 kittens at birth. Transferred IgG and IgA decreased rapidly with half-lives of 4.4 +/- 3.57 and 1.93 +/- 1.94 days, respectively. Serum IgM concentration increased irregularly during the first week of life, followed by a steady increase. Foreign IgG given up to 12 hours after birth was detected in kittens' serum, whereas IgG given at or after 16 hours was not found in any kitten's serum. CONCLUSIONS: Milk and colostral immunoglobulin concentrations did not differ significantly. The half-lives of maternally derived IgG and IgA in kittens were shorter than those reported in dogs. IgG given at or after 16 hours of life was not absorbed by neonatal kittens. CLINICAL RELEVANCE: Queen's milk obtained anytime during lactation may be used as a replacement for colostrum as a source of antibodies for neonatal kittens. Kittens at risk for neonatal isoerythrolysis must only be removed from the queens during the first day of life.

Animals↗

PubMed1995

Inheritance of cystinuria and renal defect in Newfoundlands.

OBJECTIVE: To describe clinical features, characterize metabolic renal abnormalities, and evaluate mode of inheritance of cystinuria in Newfoundlands. DESIGN: Prospective study. ANIMALS: Two families of Newfoundlands including 11 dogs with dysuria, stranguria, or obstruction attributable to cystine calculi. PROCEDURE: Urinalysis and nitroprusside spot tests were performed to evaluate cystinuria in the affected dogs. All calculi were analyzed by crystallography. Amino acid concentrations in urine and plasma of affected dogs were compared with those in clinically normal related dogs. Renal fractional excretion and reabsorption of amino acids were determined in 5 affected Newfoundlands. RESULTS: Nine dogs had pure cystine calculi in the bladder, and 4 of these had renal cystine calculi. Affected dogs persistently excreted excessive amounts of cystine (> 500 nmol/mg of creatinine; reference = 54 +/- 38 nmol/mg of creatinine) and had typical cystine crystals in acidic urine. Urinary excretion of ornithine, lysine, and arginine was also high. Dogs with cystinuria had complete lack of reabsorption and active secretion of cystine, and reabsorption of lysine, ornithine, and arginine was moderately impaired. Although clinical signs of urinary obstruction were observed only in males, cystinuric male and female offspring were produced from noncystinuric parents, consistent with an autosomal recessive mode of inheritance. Obligate heterozygotes did not have clinical signs, and had normal urinary cystine content and renal amino acid reabsorption. CLINICAL IMPLICATIONS: Because detection of carriers by routine urinalysis is currently not possible, Newfoundlands with cystinuria and their parents and offspring should be excluded from breeding.

Animals↗

PubMed1995

A single nucleotide insertion in the canine interleukin-2 receptor gamma chain results in X-linked severe combined immunodeficiency disease.

The immunologic and genetic analysis of a 14-week-old-male cardigan Welsh corgi puppy that presented with failure to thrive, diarrhea, and intermittent vomiting are described. The lack of palpable lymph nodes, the premature death of a male sibling, and similar clinical signs in a male cousin suggested that a primary immunodeficiency disease might be responsible for his poor clinical condition. Quantitation of serum immunoglobulins revealed low concentrations of IgG and undetectable IgA, yet normal concentrations of IgM. A complete blood cell count showed a slight anemia and lymphopenia. Although the peripheral blood contained a normal percentage of T cells, with an increased CD4:CD8 ratio, they were unable to proliferate in response to phytohemagglutinin (PHA) and/or interleukin 2 (IL-2). Furthermore, following PHA activation, the peripheral blood lymphocytes (PBL) demonstrated a nearly complete lack of IL-2 binding. All of these laboratory findings were identical with our previous findings from dogs with X-linked severe combined immunodeficiency (XSCID) that is due to a mutation in their IL-2 receptor gamma (IL-2R gamma) chain. Examination of the corgi's IL-2R gamma cDNA revealed an insertion of a cytosine following nucleotide 582, resulting in a premature stop codon prior to the transmembrane domain. The insertion also created an EcoO109 restriction enzyme site that enabled us to detect the mutation in the patient's genomic DNA. This new mutation in the IL-2R gamma chain discovered in a cardigan Welsh corgi puppy results in XSCID with similar immunologic abnormalities as observed in dogs with the same disease resulting from a different IL-2R gamma chain mutation.

Amino Acid Sequence↗

PubMedDate not supplied

X-linked ectodermal dysplasia in the dog.

A male German shepherd pup had symmetrical areas of hairlessness as well as missing and misshapen teeth. There was no family history of a similar phenotype. In biopsies of the hairless skin and foot pads there were no hair follicles, adnexal structures, or eccrine glands. These findings resemble those in ectodermal dysplasia in the Tabby mouse and anhidrotic/hypohidrotic ectodermal dysplasia (HED) in man, which are both X-linked recessive disorders and thought to be homologous gene defects. While similar cases of ectodermal dysplasia have been reported in the dog and some genetic studies carried out, definitive confirmation of X-linked inheritance of canine ectodermal dysplasia is lacking. Family studies and experimental matings using the propositus gave results that confirm X-linked recessive inheritance. On statistical grounds, it is concluded that ED in the propositus is due to a new mutation. A colony of dogs with this mutation is maintained for further study.

Animals↗