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Biomedical subjects

M W Jackson

Publications and source records attributed to M W Jackson.

At least 19 recordsLinked to original sources
PubMed2007

Autoantibody-mediated bladder dysfunction in type 1 diabetes.

Bladder dysfunction is a common complication of diabetic autonomic neuropathy; however, its cause remains uncertain. We have recently identified a novel IgG autoantibody (Ab) in patients with type 1 diabetes that acts as an agonist at the dihydropyridine (DHP) site of L-type voltage-gated calcium channels (VGCC), disrupting neuronal regulation of visceral smooth muscle. In the present study, passive transfer to mice of IgG from patients with type 1 diabetes was used to investigate the role of anti-VGCC Abs in mediating diabetic bladder dysfunction. Injection of mice with diabetic immunoglobulin (IgG) with anti-VGCC activity induced features of an overactive bladder, including phasic detrusor contractions and a loss of bladder wall compliance. The bladder overactivity is mimicked by the DHP agonist Bay K8644, reversed by the DHP antagonist nicardipine, but is insensitive to the motor nerve blocker tetrodotoxin, indicating that the anti-VGCC Ab acts at the level of the bladder detrusor itself. This study reports the first evidence of Ab-mediated bladder dysfunction in type 1 diabetes, which may be part of a wider spectrum of smooth muscle and cardiac abnormalities.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2004

Costs and benefits of cold tolerance in transgenic Arabidopsis thaliana.

Cold tolerance in plants is an ecologically important trait that has been under intensive study for basic and applied reasons. Determining the fitness benefits and costs of cold tolerance has previously been difficult because cold tolerance is normally an induced trait that is not expressed in warm environments. The recent creation of transgenic plants constitutively expressing cold tolerance genes enables the investigation of the fitness consequences of cold tolerance in multiple temperature environments. We studied three genes from the CBF (C-repeat/dehydration responsive element binding factor) cold tolerance pathway, CBF1, 2 and 3, in Arabidopsis thaliana to test for benefits and costs of constitutive cold tolerance. We used multiple insertion lines for each transgene and grew the lines in cold and control conditions. Costs of cold tolerance, as determined by fruit number, varied by individual transgene. CBF2 and 3 overexpressers showed costs of cold tolerance, and no fitness benefits, in both environments. CBF1 overexpressing plants showed no fitness cost of cold tolerance in the control environment and showed a marginal fitness benefit in the cold environment. These results suggest that constitutive expression of traits that are normally induced in response to environmental stress will not always lead to costs in the absence of that stress, and that the ecological risks of CBF transgene escape should be assessed prior to their use in commercial agriculture.

Adaptation, Physiological↗
PubMed2003

Evaluation of the clinical and allergen specific serum immunoglobulin E responses to oral challenge with cornstarch, corn, soy and a soy hydrolysate diet in dogs with spontaneous food allergy.

Fourteen dogs with known clinical hypersensitivity to soy and corn were maintained on a limited antigen duck and rice diet until cutaneous manifestations of pruritus were minimal (78 days). Sequential oral challenges with cornstarch, corn and soy were then performed. Subsequently, the dogs were fed a diet containing hydrolysed soy protein and cornstarch. Throughout the study period the dogs were examined for cutaneous manifestations of pruritus and, additionally, serum was collected for measurement of allergen-specific and total immunoglobulin (Ig)E concentrations. Intradermal testing with food antigens was performed prior to entry into the study and after 83 days. A statistically significant clinical improvement was measured between days 0 and 83. Significant pruritus was induced after oral challenge with cornstarch, corn and soy (P = 0.04, 0.002, 0.01, respectively) but not with the hydrolysed diet (P = 0.5). The positive predictive value of the skin test for soy and corn allergy was reduced after feeding a soy and corn free diet. Although increases in soy and corn-specific serum IgE concentrations were measured in individual dogs post challenge they were not statistically significant and could not be used to predict clinical hypersensitivity.

Animal Feed↗
PubMed2001

Secondary hypoparathyroidism attributed to hypomagnesemia in a dog with protein-losing enteropathy.

Severe hypomagnesemia (0.8 mg/dl; reference range, 1.6 to 2.3 mg/dl), hypocalcemia, and protein-losing enteropathy were identified in a 5-year-old castrated male 3-kg (6.6 lb) Shih Tzu examined because of anorexia, lethargy, paresis, and abdominal distention. Histologic examination of intestinal biopsy specimens revealed lymphangiectasia and lymphocytic, plasmacytic, neutrophilic infiltrates. Initial treatment included administration of magnesium (0.80 mEq/kg [0.36 mEq/lb]) of body weight in a balanced electrolyte solution. This treatment resulted in normalization of the serum magnesium concentration (1.7 mg/dl); resolution of the lethargy, paresis, and tachycardia; and an increase in the serum parathyroid hormone and ionized calcium concentrations. Findings were consistent with secondary hypoparathyroidism attributable to hypomagnesemia. Magnesium concentration should be monitored in all dogs with gastrointestinal tract disease, especially those with protein-losing enteropathy, anorexia, and weakness.

Animals↗
PubMed2001

MdmX binding to ARF affects Mdm2 protein stability and p53 transactivation.

Regulation of p53 involves a complex network of protein interactions. The primary regulator of p53 protein stability is the Mdm2 protein. ARF and MdmX are two proteins that have recently been shown to inhibit Mdm2-mediated degradation of p53 via distinct associations with Mdm2. We demonstrate here that ARF is capable of interacting with MdmX and in a manner similar to its association with Mdm2, sequestering MdmX within the nucleolus. The sequestration of MdmX by ARF results in an increase in p53 transactivation. In addition, the redistribution of MdmX by ARF requires that a nucleolar localization signal be present on MdmX. Although expression of either MdmX or ARF leads to Mdm2 stabilization, coexpression of both MdmX and ARF results in a decrease in Mdm2 protein levels. Similarly, increasing ARF protein levels in the presence of constant MdmX and Mdm2 leads to a dose-dependent decrease in Mdm2 levels. Under these conditions, ARF can synergistically reverse the ability of Mdm2 and MdmX to inhibit p53-dependent transactivation. Finally, the association and redistribution of MdmX by ARF has no effect on the protein stability of either ARF or MdmX. Taken together, these results demonstrate that the interaction between MdmX and ARF represents a novel pathway for regulating Mdm2 protein levels. Additionally, both MdmX and Mdm2, either individually or together, are capable of antagonizing the effects of the ARF tumor suppressor on p53 activity.

Amino Acid Sequence↗
PubMed2000

Interactions between type III secretion apparatus components from Yersinia pestis detected using the yeast two-hybrid system.

Interactions among the Yersinia secretion (Ysc) proteins of Yersinia pestis were explored using the yeast two-hybrid system. Various pairwise combinations of the yscEFGHIKLN and Q genes fused to the DNA-binding or activation domain of the yeast GAL4 gene were introduced into yeast, and expression of a reporter gene encoding beta-galactosidase was detected. Combinations of yscN and yscL, yscL and yscQ, and yscQ and yscK resulted in high levels of reporter gene activation. These results suggest that YscL interacts with both YscN and YscQ, and that YscQ interacts with both YscL and YscK. Three-hybrid analyses using plasmid pDELA to target a third hybrid protein to the yeast nucleus was used to detect the formation of ternary protein complexes. Using the three-hybrid system, YscQ expressed from plasmid pDELA was able to bring together the YscK and YscL fusion proteins. In a similar manner, YscL expressed from plasmid pDELA was able to bring together the YscN and YscQ fusion proteins. Together, these results suggest that a complex composed of YscN, YscQ, YscK and YscL is involved in the assembly and/or function of the Y. pestis type III secretion apparatus.

Bacterial Proteins↗
PubMed2000

MdmX protects p53 from Mdm2-mediated degradation.

The p53 tumor suppressor protein is stabilized in response to cellular stress, resulting in activation of genes responsible for either cell cycle arrest or apoptosis. The cellular pathway for releasing normal cells from p53-dependent cell cycle arrest involves the Mdm2 protein. Recently, a p53-binding protein with homology to Mdm2 was identified and called MdmX. Like Mdm2, MdmX is able to bind p53 and inhibit p53 transactivation; however, the ability of MdmX to degrade p53 has yet to be examined. We report here that MdmX is capable of associating with p53 yet is unable to facilitate nuclear export or induce p53 degradation. In addition, expression of MdmX can reverse Mdm2-targeted degradation of p53 while maintaining suppression of p53 transactivation. Using a series of MdmX deletions, we have determined that there are two distinct domains of the MdmX protein that can stabilize p53 in the presence of Mdm2. One domain requires MdmX interaction with p53 and results in the retention of both proteins within the nucleus and repression of p53 transactivation. The second domain involves the MdmX ring finger and results in stabilization of p53 and an increase in p53 transactivation. The potential basis for stabilization and increased p53 transactivation by the MdmX ring finger domain is discussed. Based on these observations, we propose that the MdmX protein may function to maintain a nuclear pool of p53 protein in undamaged cells.

3T3 Cells↗
PubMed1999

Constitutive mdmx expression during cell growth, differentiation, and DNA damage.

The mdmx gene was shown to possess high homology to the mdm-2 gene and to encode a protein that can bind p53 and block p53 transactivation. Because Mdm-2 protein blocks the growth-suppressive activity of the p53 tumor-suppressor protein through similar activities, we examined the expression patterns of mdmx to determine how MdmX expression correlates with p53 protein levels. In this study, the expression pattern and protein levels of mdmx were examined in a number of cell culture systems. Like mdm-2, mdmx gene expression was constitutive during serum deprivation/restimulation of murine fibroblasts and differentiation of either murine teratocarcinoma or preadipocyte cells. In contrast, whereas mdm-2 gene expression was induced after cisplatin damage to ovarian carcinoma cells, mdmx expression remained constitutive. Because p53 transactivation is critical following a genotoxic stress, we examined p53:MdmX complexes after in vitro DNA-PK phosphorylation, a posttranslational modification that blocks p53 association with Mdm-2. The DNA-PK phosphorylation of p53 was capable of inhibiting p53:MdmX association. Thus, whereas DNA damage does not regulate mdmx mRNA levels, posttranslational modifications induced during DNA damage may block p53:MdmX association in vivo. These results demonstrate that, in the cell lines examined, mdmx gene expression remains constitutive during cell proliferation and differentiation or following DNA damage. Taken together, the data suggest that cells retain a constant level of MdmX. Thus, in undamaged cells, there exists the potential for an MdmX:p53 reservoir.

3T3 Cells↗
PubMed1999

DsbA is required for stable expression of outer membrane protein YscC and for efficient Yop secretion in Yersinia pestis.

The role of the periplasmic disulfide oxidoreductase DsbA in Yop secretion was investigated in Yersinia pestis. A Y. pestis dsbA mutant secreted reduced amounts of the V antigen and Yops and expressed reduced amounts of the full-sized YscC protein. Site-directed mutagenesis of the four cysteine residues present in the YscC protein resulted in defects similar to those found in the dsbA mutant. These results suggest that YscC contains at least one disulfide bond that is essential for the function of this protein in Yop secretion.

Bacterial Outer Membrane Proteins↗
PubMed1998

YscB of Yersinia pestis functions as a specific chaperone for YopN.

Following contact with a eucaryotic cell, Yersinia species pathogenic for humans (Y. pestis, Y. pseudotuberculosis, and Y. enterocolitica) export and translocate a distinct set of virulence proteins (YopE, YopH, YopJ, YopM, and YpkA) from the bacterium into the eucaryotic cell. During in vitro growth at 37 degrees C in the presence of calcium, Yop secretion is blocked; however, in the absence of calcium, Yop secretion is triggered. Yop secretion occurs via a plasmid-encoded type III, or "contact-dependent," secretion system. The secreted YopN (also known as LcrE), TyeA, and LcrG proteins are necessary to prevent Yop secretion in the presence of calcium and prior to contact with a eucaryotic cell. In this paper we characterize the role of the yscB gene product in the regulation of Yop secretion in Y. pestis. A yscB deletion mutant secreted YopM and V antigen both in the presence and in the absence of calcium; however, the export of YopN was specifically reduced in this strain. Complementation with a functional copy of yscB in trans completely restored the wild-type secretion phenotype for YopM, YopN, and V antigen. The YscB amino acid sequence showed significant similarities to those of SycE and SycH, the specific Yop chaperones for YopE and YopH, respectively. Protein cross-linking and immunoprecipitation studies demonstrated a specific interaction between YscB and YopN. In-frame deletions in yopN eliminating the coding region for amino acids 51 to 85 or 6 to 100 prevented the interaction of YopN with YscB. Taken together, these results indicate that YscB functions as a specific chaperone for YopN in Y. pestis.

Amino Acid Sequence↗
PubMed1997

Overexpression of FGF-2 modulates fiber cell differentiation and survival in the mouse lens.

During mammalian embryogenesis, the ocular lens forms through a temporally and spatially regulated pattern of differentiation which is thought to be coordinated at least in part by the FGF-1 and FGF-2 members of the fibroblast growth factor (FGF) family. Previous transgenic experiments in which FGF-1 or dominant negative FGF receptors were overexpressed in the lens indicated that FGF-1 could induce differentiation while differentiated lens cells rely upon FGF signaling for their survival. In this study, we asked if the 17.5 kDa FGF-2 protein was capable of inducing differentiation of lens cells in transgenic mice. Unexpectedly, differentiation was inhibited by lens-specific expression of a transgene encoding a secreted form of the 17.5 kDa bovine FGF-2 protein under the transcriptional control of the murine alphaA-crystallin promoter (alphaAIgFGF-2 transgenic mice). To address the possibility that FGF-2 functions as a modulator of fiber cell survival, alphaAIgFGF-2 transgenic mice were crossed to transgenic mice exhibiting extensive apoptosis in the lens due to the functional inactivation of the retinoblastoma protein (alphaAE7 transgenic mice). The level of apoptosis in the lenses of double transgenic mice was substantially reduced as compared to the level in lenses from alphaAE7 only mice. These studies indicate that FGF-2 can act as a modulator of the later stages of differentiation including fiber cell survival. Additionally, they imply that control of lens development by FGFs is a complex process in which FGF-1 and FGF-2 play distinct roles.

Animals↗
PubMed1997

Vascular endothelial growth factor (VEGF) expression in prostate cancer and benign prostatic hyperplasia.

PURPOSE: Vascular endothelial growth factor (VEGF) is a potent inducer of endothelial cell growth and is expressed at elevated levels in several tumor types. In this study immunohistochemical localization and distribution of isoforms of VEGF were examined in malignant and non-malignant human prostatic tissues. MATERIALS AND METHODS: Immunohistochemical localization of VEGF was performed on thirty well, moderately and poorly differentiated stage D2 prostate cancer specimens and twenty benign prostatic hyperplasia (BPH) specimens. VEGF mRNA was determined by polymerase chain reaction and VEGF protein isoforms were detected by Western blotting of prostate cancer and BPH specimens. RESULTS: Cytoplasmic immunoreactivity for VEGF was detected in tumor cells and peritumoral stromal cells of prostate cancer specimens and in non-malignant glandular epithelial cells and interglandular stromal cells in BPH specimens. Staining was focal with areas of strongly to weakly stained cells adjacent to negatively staining areas. mRNA's for VEGF121, VEGF165 and VEGF189 were present in all benign and malignant prostate specimens. VEGF protein isoforms of molecular sizes corresponding to VEGF165 and VEGF189 were detected in cytosolic extracts of prostate cancers and BPH specimens by Western blotting. In addition, two novel higher molecular weight immunoreactive bands were detected in the prostate specimens. CONCLUSIONS: Widespread distribution of VEGF in prostate cancers and BPH specimens suggest that the VEGF165, VEGF189 isoforms and novel 90 and 110 kD forms detected may contribute to the establishment or progression of these conditions.

Blotting, Western↗
PubMed1996

The ABL-MYC retrovirus generates antigen-specific plasmacytomas by in vitro infection of activated B lymphocytes from spleen and other murine lymphoid organs.

ABL-MYC is a recombinant retrovirus that constitutively expresses the v-abl and c-myc oncogenes. When used to infect immunized mice this virus rapidly and efficiently induces plasmacytomas of which an unusually high percentage secrete antigen (Ag)-specific monoclonal antibodies. These findings suggested that ABL-MYC targets Ag-stimulated B cells for transformation and that infection of lymphoid cells in vitro might be a useful, alternative method for generating monoclonal, Ag-specific plasmacytomas (ASPCTs). Therefore, we used helper virus-free ABL-MYC to infect suspensions of cells from spleens and other lymphoid organs from mice that had been immunized with a variety of Ags and transplanted them into naive mice. The results show that ABL-MYC preferentially transforms splenocytes that are Ag-reactive. They also demonstrate that ASPCTs can be produced by in vitro infection of cell suspensions from the spleen, lymph nodes and Peyer's patches of mice that had been immunized intraperitoneally with sheep red blood cells, Escherichia coli core RNA polymerase or Epstein-Barr virus gp340 protein or immunized orally with live Giardia lamblia parasites. The ASPCTs usually consisted of one to three colnes, secreted antibodies that were quantitatively and qualitatively similar to those obtained from hybridomas, and could continue to secrete Ag-reactive antibody over eight transplant generations.

Animals↗
PubMed1996

Foveolar hyperplasia following partial gastrectomy results from expansion of surface mucous cell compartment.

Antrectomy with gastroenterostomy reconstruction is often associated with the development of foveolar hyperplasia and oxyntic atrophy. While a role for bile reflux in the etiology of foveolar hyperplasia is well established, the identity of the mucous cell lineages responsible for this condition have not been well characterized. We have studied three patients who demonstrated foveolar hyperplasia in their gastric remnant following antrectomy and gastroenterostomy. Mucosal samples were stained with antibodies against the trefoil peptides pS2 and hSP, to identify surface mucous and mucous neck cell lineages, respectively. Postoperative biopsies from all three patients showed oxyntic atrophy as documented by staining of parietal cells with antibodies against H/K-ATPase. All three patients demonstrated an exclusive expansion of pS2 immunoreactive mucous cells. The hSP staining cells were located deep in the expanded foveolar region. The results suggest that foveolar hyperplasia following antrectomy with gastroenterostomy results from a reactive hyperplasia of surface mucous cells. This pattern of surface cell hyperplasia is more consistent with a reactive expansion of mucous cells than with a response to chronic injury.

Adult↗
PubMed1994

Administration of vancomycin for treatment of ascending bacterial cholangiohepatitis in a cat.

A 12-year-old neutered male domestic shorthair cat, being treated with methimazole for hyperthyroidism, developed chronic cholangitis with portal fibrosis and chronic cholecystitis. The common bile duct was not patent, which necessitated cholecystojejunostomy. Four days after surgery, the cat developed suppurative cholangio-hepatitis caused by a beta-lactam resistant Enterococcus. The cat's condition was further complicated by the concurrent development of hypokalemic polymyopathy. On the basis of minimum inhibitory concentrations, the Enterococcus was determined to be susceptible to vancomycin and resistant to numerous antibiotics commonly used for treatment of infections caused by Enterococcus spp. The cat recovered without evidence of adverse effects attributable to vancomycin.

Animals↗
PubMed1994

Primary IgG secreting plasma cell tumor in the gastrointestinal tract of a dog.

A mixed-breed dog, evaluated because of a chronic history of diarrhea and intestinal bleeding, was found to have a multilobular mass involving the intestine. Surgical resection of the mass necessitated an ileocolic anastomosis. On the basis of histologic and electron microscopic appearance and staining characteristics, a tentative diagnosis of intestinal carcinoid was made. Recovery was uncomplicated; the owners declined further diagnostic tests or treatment. Eight weeks later, the dog was reexamined because of signs consistent with hyperviscosity syndrome and hyperproteinemia. At the owner's request, the dog was euthanatized. At necropsy, extensive metastases to liver and lymph nodes, but not to bone, were seen. Reevaluation of the intestinal mass supported classifying the tumor as an IgG-secreting extramedullary plasmacytoma. This case underscores the need for additional histologic techniques, especially when confronted with an unusual manifestation of hyperproteinemia.

Animals↗
PubMed1993

Nutritional management of cats with infectious disease.

The effect of malnutrition in patients with a variety of ailments is known to be deleterious to their overall quality of life, response and tolerance to therapy, and ultimate survival. These effects may be amplified in feline patients with infectious disease owing to the blunting of immunologic responsiveness that results from malnutrition. This vicious cycle of infection, ensuing malnutrition, and subsequent immunocompromise may not allow the patient to mount an attack on the invading pathogen adequately. The most logical means to reverse this cycle is to ensure an adequate nutritional state in the patient. Initial attempts at maintaining or increasing voluntary oral intake should be initiated in the short term. However, enteral or parenteral support should be instituted as quickly as possible if these should fail. Much is yet to be discerned about specific optimal supplementation techniques and dietary formulations for feline patients; however, the application of relatively simple and general principles of nutritional support offer our feline patients with infectious disease the best opportunity to overcome their disease.

Animal Nutritional Physiological Phenomena↗