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Biomedical subjects

L Garrett

Publications and source records attributed to L Garrett.

At least 37 records · Page 2Linked to original sources
PubMed1997

Cre-mediated gene deletion in the mammary gland.

To delete genes specifically from mammary tissue using the Cre-lox system, we have established transgenic mice expressing Cre recombinase under control of the WAP gene promoter and the MMTV LTR. Cre activity in these mice was evaluated by three criteria. First, the tissue distribution of Cre mRNA was analyzed. Second, an adenovirus carrying a reporter gene was used to determine expression at the level of single cells. Third, tissue specificity of Cre activity was determined in a mouse strain carrying a reporter gene. In adult MMTV-Cre mice expression of the transgene was confined to striated ductal cells of the salivary gland and mammary epithelial cells in virgin and lactating mice. Expression of WAP-Cre was only detected in alveolar epithelial cells of mammary tissue during lactation. Analysis of transgenic mice carrying both the MMTV-Cre and the reporter transgenes revealed recombination in every tissue. In contrast, recombination mediated by Cre under control of the WAP gene promoter was largely restricted to the mammary gland but occasionally observed in the brain. These results show that transgenic mice with WAP-Cre but not MMTV-Cre can be used as a powerful tool to study gene function in development and tumorigenesis in the mammary gland.

Adenoviridae↗
PubMed1997

Rescue of osteoclast function by transgenic expression of kinase-deficient Src in src-/- mutant mice.

The Src tyrosine kinase has been implicated in a wide variety of signal transduction pathways, yet despite the nearly ubiquitous expression of c-src, src-/- mice show only one major phenotype-osteopetrosis caused by an intrinsic defect in osteoclasts, the cells responsible for resorbing bone. To explore further the role of Src both in osteoclasts and other cell types, we have generated transgenic mice that express the wild-type and mutated versions of the chicken c-src proto-oncogene from the promoter of tartrate resistant acid phosphatase (TRAP), a gene that is expressed highly in osteoclasts. We demonstrate here that expression of a wild-type transgene in only a limited number of tissues can fully rescue the src-/- phenotype. Surprisingly, expression of kinase-defective alleles of c-src also reduces osteopetrosis in src-/- animals and partially rescues a defect in cytoskeletal organization observed in src-/- osteoclasts. These results suggest that there are essential kinase-independent functions for Src in vivo. Biochemical examination of osteoclasts from these mice suggest that Src may function in part by recruiting or activating other tyrosine kinases.

Acid Phosphatase↗
PubMed1997

Stat5a is mandatory for adult mammary gland development and lactogenesis.

Prolactin (PRL) induces mammary gland development (defined as mammopoiesis) and lactogenesis. Binding of PRL to its receptor leads to the phosphorylation and activation of STAT (signal transducers and activators of transcription) proteins, which in turn promote the expression of specific genes. The activity pattern of two STAT proteins, Stat5a and Stat5b, in mammary tissue during pregnancy suggests an active role for these transcription factors in epithelial cell differentiation and milk protein gene expression. To investigate the function of Stat5a in mammopoiesis and lactogenesis we disrupted this gene in mice by gene targeting. Stat5a-deficient mice developed normally and were indistinguishable from hemizygous and wild-type littermates in size, weight, and fertility. However, mammary lobuloalveolar outgrowth during pregnancy was curtailed, and females failed to lactate after parturition because of a failure of terminal differentiation. Although Stat5b has a 96% similarity with Stat5a and a superimposable expression pattern during mammary gland development it failed to counterbalance for the absence of Stat5a. These results document that Stat5a is the principal and an obligate mediator of mammopoietic and lactogenic signaling.

Animals↗
PubMed1997

Trinucleotide repeats (CGG)22TGG(CGG)43TGG(CGG)21 from the fragile X gene remain stable in transgenic mice.

Unstable premutation alleles in fragile X contain CGG repeats ranging from 34 to about 200. To study the mechanism of formation and the behavior of dynamic mutations, we constructed and cloned 88 trinucleotide repeats including 43 uninterrupted CGGs and injected them into mouse fertilized oocytes. We analyzed 342 transgenic animals obtained from 6 different founders after one to four generations, and found that the repeats remained stable regardless of the sex of the transmitting mouse. Therefore, we may need to consider factors other than trinucleotide repeat length alone to explain CGG instability and create an animal model.

Animals↗
PubMed1994

Prostate and mammary adenocarcinoma in transgenic mice carrying a rat C3(1) simian virus 40 large tumor antigen fusion gene.

A transgenic mouse model for prostate and mammary cancer has been developed in mice containing a recombinant gene expressing the simian virus 40 early-region transforming sequences under the regulatory control of the rat prostatic steroid binding protein [C3(1)] gene. Male transgenic mice develop prostatic hyperplasia in early life that progresses to adenoma or adenocarcinoma in most animals surviving to longer than 7 months of age. Prostate cancer metastases to lung have been observed. Female animals from the same founder lines generally develop mammary hyperplasia by 3 months of age with subsequent development of mammary adenocarcinoma by 6 months of age in 100% of the animals. The development of tumors correlates with the expression of the transgene as determined by Northern blot and immunohistochemical analyses. The results of these experiments demonstrate that the C3(1) regulatory region used in these experiments is useful for targeting expression to the prostate and mammary gland. To our knowledge, this experimental system is the first reported transgenic mouse model for prostate cancer. These transgenic animals offer the opportunity to study hormone response elements in vivo and the multistage progression from normal tissue to carcinoma in the prostate and mammary glands.

Adenocarcinoma↗
PubMed1993

Characterization of human keratinocytes transformed by high risk human papillomavirus types 16 or 18 and herpes simplex virus type 2.

Recent reports implicate two DNA tumour viruses, herpes simplex virus type 2 (HSV-2) and human papillomavirus types 16 or 18 (HPV-16 and -18), in the pathogenesis of cervical cancer. Previous studies have indicated that primary human fibroblasts transfected with HPV-16 and HSV-2 morphological transforming region III (mtr III) are more aneuploid than fibroblasts immortalized with HPV-16 and that HSV-2 DNA sequences are retained in transformed cells. Since HSV-2 and HPV typically infect cells of epithelial origin, the interactions of these viruses with respect to morphological transformation were examined in human keratinocytes. HPV-16- or HPV-18-immortalized keratinocytes (FEPL and FEA cells, respectively) were transfected with fragments derived from HSV-2 mtr III. When compared to their normal counterparts, FEPL cells and FEA cells transfected with mtr III fragments grew to higher saturation densities and were morphologically transformed. FEPL cells transformed by HSV-2 were capable of growth in soft agar and, when injected into nu/nu mice, lesions developed at the site of injection. Histological examination of the lesions revealed a benign mass which was composed of squamous epithelial cells that were producing keratin. In contrast, immortalized keratinocytes (FEPL or FEA) or FEA cells transfected with HSV-2 did not produce these lesions. These observations suggest that sequences within mtr III can alter the growth properties of human keratinocytes immortalized by HPV-16 or HPV-18.

Animals↗
PubMed1992

Numbers and proportions of unmyelinated axons at cervical levels in the fasciculus gracilis of monkey and cat.

The present study is a quantitative analysis of the unmyelinated fiber population in the fasciculus gracilis of the second cervical segment of cat and monkey. We find that unmyelinated fibers represent 13.7% of the total fiber population in this pathway in the cat and 18.9% in the monkey (Macaca fascicularis). The existence of such large numbers of these axons suggests that there may be a sizeable ascending fine primary afferent pathway in the fasciculus gracilis in cat and monkey whose destination is presumably the dorsal column nuclei. These findings are of interest in regard to classic ideas that the afferent fibers in the dorsal columns are large myelinated fibers that convey fine discriminative information to the dorsal column nuclei.

Animals↗
PubMed1990

Low level amplification of c-sis and c-myc in a spontaneous osteosarcoma model.

Canine and human osteosarcoma are very similar clinically, radiologically and pathologically. DNA extracted from canine osteosarcomas (n = 9) and normal canine control tissues (n = 17) was examined for amplification of the c-sis, c-myc, N-myc and c-H-ras protooncogenes. Statistically significant amplification of the c-sis and c-myc protooncogenes was evident in the tumor tissues as compared to the normal control tissues (P less than 0.05). DNA and total cellular RNA from cultured canine and human osteosarcoma and fibroblast cell lines were examined for amplification or enhanced expression of c-sis and c-myc. Very low levels of c-myc and c-sis DNA amplification were noted in canine osteosarcoma cells as compared to canine fibroblasts. Immunostaining of sections of human and canine osteosarcoma for the sis gene product, PDGF B, showed similar levels and patterns of expression in both populations of tumors.

Animals↗
PubMed1989

Beneficial effects of vitamin C on risk factors of cardiovascular diseases.

The aim of this investigation is to study the hypothesis that vitamin C has beneficial effects on some risk factors of cardiovascular diseases. Sixty-seven volunteers participated in this study. Thirty and thirty-seven subjects were assigned randomly to two groups. The first was given a placebo and the second was given a vitamin C, respectively. Both regimens were followed for six months. The dose of vitamin C was 500 mg/day. Double blind technique was used throughout the study. These data supported part of the beneficial effects of vitamin C on atherosclerosis process, i.e. reduce significantly body fat, systolic blood pressure, and pulse, and increase significantly high density lipoprotein. On the other hand, these data did not show favourable effects on other lipid parameters, i.e. cholesterol, triglyceride, low density lipoprotein, and very low density lipoprotein.

Ascorbic Acid↗
PubMed1982

The long-term patient in the community: life style patterns and treatment implications.

A sample of 99 long-term patients at an urban community mental health-mental retardation center were interviewed to determine how they spent their time and their degree of happiness with their lives and the services they received at the center. More than half the patients were considered by center staff to be only mildly or moderately impaired, but as a group they were distinguished by low levels of educational, financial, and vocational achievement; only 13 per cent were working more than half time. Most of the patients considered themselves happy, but their life style was oriented toward health and social relationships and lacked a work-task orientation. The authors conclude that the patients' life style meshes closely with the orientation of the treatment system; neither places emphasis on achievement of noninterpersonal tasks or enhancement of a work orientation. The authors believe that many chronic users of community mental health services have the potential to work and that practically all could benefit from the ego-enhancing experiences resulting from the successful accomplishment of tasks and development of skills. Therefore they feel programming for long-term patients should address deficits in work and achievement motivation.

Activities of Daily Living↗
PubMed1979

Chronically reserpinized rat as a model for cystic fibrosis: Na+ transport inhibitory effect in submaxillary saliva.

The retrograde perfusion assay in the rat parotid gland was used to investigate the effects of salivary secretions from control and reserpine-treated rats on Na+ reabsorption. Results demonstrated that submaxillary saliva from the treated animals caused a 69% inhibition of Na+ reabsorption, accompanied by a 28% reduction in the volume of saliva secreted, and a 22% reduction in flow rate. By contrast, submaxillary saliva from control rats caused a 6% inhibition of Na+ reabsorption, a 6% reduction in volume, and a 5% reduction in flow rate. Parotid saliva from reserpine-treated rats also inhibited Na+ reabsorption to the extent of 39% and caused a 38% reduction in volume and a 33% reduction in flow. Parotid saliva from control rats only inhibited Na+ reabsorption to the extent of 2.7% and caused a 4--6% reduction in salivary volumes and flow rates. The inhibition of Na+ reabsorption and the reduction in salivary volume and flow rates caused by submaxillary saliva of reserpine-treated rats were either abolished or significantly reduced when the saliva was previously heated to 100 degrees C, frozen, and then thawed or kept in glass tubes at 4 degrees C for 24 hr. These results indicate that saliva from reserpine-treated rats have comparable effects in this assay system to those of saliva from cystic fibrosis (CF) patients and further support its use as an animal model for this disease.

Animals↗
PubMed1975

Effect of chest strapping on regional lung function.

We studied lung mechanics and regional lung function in five young men during restrictive chest strapping. The effects on lung mechanics were similar to those noted by others in that lung elastic recoil increased as did maximum expiratory flow at low lung volumes. Chest strapping reduced the maximum expiratory flow observed at a given elastic recoil pressure. Breathing helium increased maximum expiratory flow less when subjects were strapped than when they were not. These findings indicated that strapping decreased the caliber of airways upstream from the equal pressure point. Regional lung volumes from apex to base were measured with xenon 133 while subjects were seated. The distribution of regional volumes was measured at RV, and at volumes equal to strapped FRC and strapped TLC; no change due to chest strapping was observed. Similarly, the regional distribution of 133Xe boluses inhaled at RV and strapped TLC was unaffected by chest strapping. Closing capacity decreased with chest strapping. We concluded that airway closure decreased during chest strapping and that airway closure was not the cause of the observed increase in elastic recoil of the lung. The combination of decreased slope of the static pressure-volume curve and unchanged regional volumes suggested that strapping increased the apex-to-base pleural pressure gradient.

Adult↗