Search PubMed⌕ Search

Biomedical subjects

C Morris

Publications and source records attributed to C Morris.

At least 55 records · Page 3Linked to original sources
PubMed2000

Complex patterns of inheritance of an imprinted murine transgene suggest incomplete germline erasure.

Here we report a transgenic mouse line that exhibits significant deviations from a classic pattern of parental imprinting. When the transgene is passed through the female germline, it is completely silenced in some offspring while in others expression is reduced. This variable expressivity does not appear to be the result of differences in the presence of unlinked modifiers. Female transmission of the transgene is associated with hypermethylation. The transgene is generally reactivated on passage through the male germline. Extended pedigrees reveal complex patterns of inheritance of the phenotype. The most likely explanation for this result is that the imprint is not completely erased and reset when passed through the germline of either sex. FISH analysis reveals that the transgene has integrated into chromosome 3 band E3, a region not known to carry imprinted genes, and the integration site shows no sign of allele-specific differential methylation. These findings, in conjunction with other recent work, raise the possibility that the introduction of foreign DNA into the mammalian genome, either through retrotransposition or transgenesis, may be associated with parental imprinting that is not always erased and reset during meiosis.

Animals↗
PubMed2000

ICI 182,780 (Faslodex): development of a novel, "pure" antiestrogen.

BACKGROUND: The nonsteroidal antiestrogen tamoxifen is well established as an effective treatment for patients with breast carcinoma, both for the treatment of metastatic disease and as an adjuvant to surgery for patients with primary breast carcinoma. In addition to exerting antagonistic effects on the estrogen receptor, tamoxifen and its derivatives act as partial agonists on certain tissues. These agonistic effects, for example, endometrial stimulation and stimulation of tumor growth after previous response to tamoxifen, may limit their clinical efficacy. ICI 182,780 (Faslodex) from AstraZeneca (Cheshire, United Kingdom) is a novel, steroidal estrogen antagonist that was designed to be devoid of estrogen agonist activity in preclinical models. METHODS: ICI 182,780 was tested in a large number of in vitro and in vivo preclinical models, and its value was assessed clinically when administered before surgery for breast carcinoma and hysterectomy for benign conditions and after failure of tamoxifen in patients with advanced breast carcinoma. RESULTS: All data indicated that ICI 182,780 is devoid of agonist activity in preclinical models and in clinical trials. It inhibits growth of the breast and endometrium. In animal models, it does not cross the blood-brain barrier and appears to be neutral with respect to lipids and bone. ICI 182,780 down-regulates the estrogen receptor and is active in tamoxifen-resistant breast carcinoma. In a small, Phase II study, durable responses were seen: Phase III clinical trials are in progress comparing ICI 182,780 with anastrozole and tamoxifen in the treatment of patients with advanced breast carcinoma. CONCLUSIONS: ICI 182,780 specifically down-regulates the estrogen receptor and, thus, represents the first of a new class of therapeutic agents. In this report, the authors present the current evidence that distinguishes ICI 182,780 from tamoxifen and related nonsteroidal compounds and establishes ICI 182,780 as the first in a new class of therapeutic agents.

Animals↗
PubMed2000

High incidence of chromosome 13 deletion in multiple myeloma detected by multiprobe interphase FISH.

Multiple myeloma (MM) is a hypoproliferative malignancy yielding informative karyotypes in no more than 30% of newly diagnosed cases. Although cytogenetic and molecular deletion of chromosome 13 is associated with poor prognosis, a MM tumor suppressor gene (TSG) has not been identified. To localize a minimal deleted region of chromosome 13, clonotypic plasma cells from 50 consecutive patients with MM were subjected to interphase fluorescence in situ hybridization (FISH) analysis using a panel of 11 probes spanning the entire long arm of chromosome 13. Whereas chromosome 13 abnormalities were absent in plasma cells from 25 normal donors, 86% of patients with MM demonstrated such aberrations. Heterogeneity, both in deletion frequency and extent, was confirmed by simultaneous FISH with 2 chromosome 13 probes. Deletion hot spots were noted at D13S272 (70%) and D13S31 (64%), 2 unlinked loci at 13q14. Homozygous deletions at these loci occurred in 12% (simultaneously in 8%) of the cases. Molecular deletions were found in all 14 patients with morphologic deletions, in 21 of 24 with uninformative karyotypes, and 8 of 12 patients with karyotype abnormalities lacking chromosome 13 deletion. Homozygous deletion of any marker was noted in 4% with low and in 36% with higher plasma cell labeling index greater than 0. 4% (P =.01). The absence of increasing deletion incidence and extent with therapy duration suggests that the observed lesions are not induced by treatment. The high incidence and extent of chromosome 13 deletions require the correlation of specific deletion(s) with poor prognosis. These analyses will provide valuable guidance toward cloning of an MM-TSG. (Blood. 2000;96:1505-1511)

Adult↗
PubMed2000

How the media do drugs: quality control and the reporting of drug issues in the UK print media.

Exaggeration, distortion, inaccuracy, sensationalism; each of these labels has been consistently applied to the reporting of drug related issues in the print and other media over the last 40 years and beyond. This research sought to understand what quality control mechanisms are employed by the UK print media in relation to issues related to illicit drugs to ensure accurate, informed and appropriate reporting. It was found that the print media in the UK employ almost no quality control mechanisms to ensure that such reporting takes place and that they predominately rely on the demonstrably insufficient qualities of the 'good reporting' skills that journalists bring to their research and writing. What concerns did exist regarding accuracy related predominately to protecting the publication from being sued for libel and no specific journalistic expertise of drug issues was considered necessary. A discussion of these issues is undertaken followed by the recommendation for the production of a negotiated media guide.

Journal Article↗
PubMed2000

Regulation of force and unloaded sliding speed in single thin filaments: effects of regulatory proteins and calcium.

1. Measurements of the unloaded sliding speed of and isometric force exerted on single thin filaments in in vitro motility assays were made to evaluate the role of regulatory proteins in the control of unloaded thin filament sliding speed and isometric force production. 2. Regulated actin filaments were reconstituted from rabbit F-actin, native bovine cardiac tropomyosin (nTm), and either native bovine cardiac troponin (nTn), troponin containing a TnC mutant, CBMII, in which the sole regulatory site in cardiac TnC (site II) is inactivated (CBMII-Tn), or troponin containing a point mutation in TnT (I79N, where isoleucine at position 79 is replaced with asparagine) associated with familial hypertrophic cardiomyopathy (FHC). 3. Addition of regulatory proteins to the thin filament increases both the unloaded sliding speed and the isometric force exerted by myosin heads on the thin filaments. 4. Variation of thin filament activation by varying [Ca2+] or the fraction of CBMII/TnC bound to the thin filament at pCa 5, had little effect on the unloaded filament sliding speed until the fraction of the thin filament containing calcium bound to TnC was less than 0.15. These results suggest that [Ca2+] primarily affects the number of attached and cycling crossbridges. 5. The presence of the FHC TnT mutant increased the thin filament sliding speed but reduced the isometric force that heavy meromyosin exerted on regulated thin filaments. These latter results, together with the increased sliding speed and isometric force seen in the presence of regulatory proteins, suggest that thin filament regulatory proteins exert significant allosteric effects on the interaction of crossbridges with the thin filament.

Actins↗
PubMed2000

18-year experience with transseptal procedures through baffles, conduits, and other intra-atrial patches.

The presence of an intra-atrial patch (IAP) has been considered a relative contraindication to transseptal puncture (TSP). The purpose of this study is to determine the efficacy and safety of the TSP through baffles, conduits, pericardial patches and other prosthetic materials in the intra-atrial septum. We reviewed the records of all pediatric patients with IAP who underwent TSP at Texas Children's Hospital from November 1979 through February 1998. The review included the cardiac diagnoses, indications for TSP, technical difficulties and follow up echocardiograms specifically addressing residual atrial shunts A total of 1958 TSP were performed. Thirty-nine patients had IAP. Cardiac diagnoses in those 39 patients included D-transposition of the great arteries after Mustard (10) or Senning procedure (6), single ventricle variant post-Fontan operation (4), total anomalous venous return repair (4), atrioventricular canal repair (9) and atrial septal defect with patch repair (6). Patients' age ranged from 1-31 years (median 7 years). The duration from the time of surgical repair to TSP ranged from 0.1-21 years (median 5 years). Indications for TSP included diagnostic and therapeutic intervention for pulmonary venous obstruction (12), creation of a baffle fenestration (2), prosthetic mitral valve evaluation (1), left ventricular outflow tract evaluation (1), access the left heart for hemodynamic evaluation (23). The IAP was traversed in 38/39 patients (97.5%), followed by diagnostic or therapeutic prograde left-heart catheterization. No complications were encountered. Follow up echocardiography in 30/38 PTS demonstrated no residual shunting across the atrial septum except for two cases in which the atrial baffle had been intentionally fenestrated. Transseptal puncture through an intra-atrial patch is a safe procedure. This technique is effective in permitting diagnostic and therapeutic left heart catheterization and does not result in residual shunting through the patch.

Adolescent↗
PubMed2000

Delayed benefits of paternal care in the burying beetle Nicrophorus vespilloides.

Burying beetles, Nicrophorus spp., inter the carcasses of small vertebrates as a food source for their offspring. Females can bury a carcass and rear a brood on it alone, but are frequently assisted by a male whose presence reduces the risk of the carcass being taken over by other beetles. However, the male often stays for longer than the carcass is vulnerable to take-over, and he cares for the brood without conferring any further benefits on it. In a laboratory experiment using N. vespilloides, we found that, in the absence of competitors, male assistance conferred no advantages on the brood for which he was caring, but significantly increased the subsequent reproductive success of his mate, in terms of the mass and rate of development of a second brood, reared alone. We suggest that this is due to a reduced parental effort of assisted females, who spent less time feeding offspring and more time resting than unassisted females whilst rearing their first broods. In the field, a female is unlikely to pair with the same male for consecutive broods, so we discuss the possible benefits a male may accrue from increasing his mate's reproductive success. We also discuss the relevance of these results to our understanding of the evolution of biparental care in birds. Copyright 2000 The Association for the Study of Animal Behaviour.

Journal Article↗
PubMed2000

Reactivation of heritably silenced gene expression in mice.

Epigenetic modifications that suppress gene activity in mammals are generally considered to be cleared in the germline, restoring totipotency of the genome. Here we report the germline inheritance of transcriptional silencing in mice, and reversion to activity after as many as three generations in the silent state. In a series of lines made with a LacZ transgene, one line exhibits variable expressivity: genotypically identical littermates have proportions of beta-Gal-positive erythrocytes that vary over at least four orders of magnitude, and in some offspring expression is completely silenced. The silent state of the transgene is inherited for multiple generations in the founder strain irrespective of the sex of the parent, implying maintenance of the epigenetic state through meiosis. Crosses of silenced mice with C57BL/6 mice result in reactivation of the transgene in approximately a third of F(1) littermates. The silencing involves a stochastic, all-or-none mechanism. Furthermore, silencing is transcriptional and correlates with methylation of the transgene as well as an inaccessible chromatin structure; these changes are reversed when expression is reactivated. This work supports the notion that silent genetic information in mammals can be inherited and later reactivated, and implies a mode of phenotypic inheritance that is less stable than Mendelian inheritance.

Animals↗
PubMed2000

Long-term outcome in congenitally corrected transposition of the great arteries: a multi-institutional study.

OBJECTIVES: The purpose of this study was to determine long-term outcome in adults with congenitally corrected transposition of the great arteries (CCTGA), with particular emphasis on systemic ventricular dysfunction and congestive heart failure (CHF). BACKGROUND: Patients with CCTGA have the anatomical right ventricle as their systemic pumping chamber, with ventricular dysfunction and CHF being relatively common in older adults. METHODS: Retrospective analysis of records of 182 patients from 19 institutions were reviewed to determine current status and possible risk factors for systemic ventricular dysfunction and CHF. Factors considered included age, gender, associated cardiac defects, operative history, heart block, arrhythmias and tricuspid (i.e., systemic atrioventricular) regurgitation (TR). RESULTS: Both CHF and systemic ventricular dysfunction were common in groups with or without associated cardiac lesions. By age 45, 67% of patients with associated lesions had CHF, and 25% of patients without associated lesions had this complication. The rates of systemic ventricular dysfunction and CHF were higher with increasing age, the presence of significant associated cardiac lesions, history of arrhythmia, pacemaker implantation, prior surgery of any type, and particularly with tricuspid valvuloplasty or replacement. Aortic regurgitation (a previously unreported problem) was also relatively common in this patient population. CONCLUSIONS: Patients with CCTGA are increasingly subject to CHF with advancing age; this complication is extremely common by the fourth and fifth decades. Tricuspid (systemic atrioventricular) valvular regurgitation is strongly associated with RV (anatomical right ventricle connected to aorta in CCTGA patients; systemic ventricle in CCTGA) dysfunction and CHF; whether it is causative or a secondary complication remains speculative.

Adult↗
PubMed2000

Hydroxychloroquine for the treatment of chronic graft-versus-host disease.

Chronic graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation. Both the disease and the medications used to treat it are associated with significant morbidity and mortality. The manifestations of chronic GVHD often resemble those of autoimmune disorders. Hydroxychloroquine (HCQ) is a 4-aminoquinoline antimalarial drug used for the treatment of autoimmune diseases. HCQ interferes with antigen processing and presentation, cytokine production, and cytotoxicity and is synergistic with cyclosporine and tacrolimus in vitro. Forty patients with steroid-resistant or steroid-dependent chronic GVHD were enrolled in a phase 2 trial of HCQ 800 mg (12 mg/kg) per day. Three complete responses and 14 partial responses were seen in 32 evaluable patients (53% response rate). All responders tolerated a >50% reduction in their steroid dose while receiving HCQ. Clinical response occurred at a median of 8 weeks (range, 4 to 24 weeks). No hematologic, hepatic, renal, or retinal toxicity was associated with HCQ. In light of its mechanisms of action, clinical activity for GVHD, and low toxicity profile, HCQ may be useful in a multiagent approach for the treatment of extensive chronic GVHD.

Adolescent↗
PubMed2000

Towards a closed eye model of the pre-ocular tear layer.

Although the tear film has been extensively studied as it exists in the open eye state, until recently very little was known as to what happens to the tear film on eye closure. Recent studies have shown that eye closure results in a profound change in the composition, origins, turnover and physiological functions of the tear film. These changes include a shift from an inducible, neurologically controlled, lacrimal secretion containing among other proteins primarily lysozyme, lactoferrin and tear specific lipocalin, to a much slower, constitutive-type of secretion, composed almost exclusively of sIgA. This change is accompanied by the build-up of sialoglycoproteins of epithelial and goblet cell origin, the build-up and activation of complement and the build-up of serum proteins. In addition, various cytokines and proinflammatory mediators accumulate, including some which are potent inducers of angiogenesis and leukochemotaxis. The closed eye also exhibits the recruitment and activation of massive numbers of PMN cells. This results in a stagnant, closed eye layer, which is extremely rich in reactive complement products, PMN cell proteases including protease-3, elastase, capthepsin G, MMP-9 and urokinase. We have postulated that this shift represents a fundamental change in host-defense strategies from a passive-barrier defense to an active immune, inflammatory, phagocyte-mediated process and that this shift is necessitated in order to protect the cornea from entrapped microorganisms. Studies have shown that autologous cell damage is avoided in closed eye tear fluid, by the accumulation of several modulators of complement activation, which shift activation towards opsonization of entrapped microorganisms and the build-up of a wide array of antiproteases. Some of the latter are likely to arise from the ocular surface tissues. Corneal neovascularization may be avoided in part by the build-up of alpha2-macroglobulin and the conversion of plasminogen to angiostatin. It is highly probable that other bioactive protein fragments are produced in the closed eye, which contribute to homeostasis. Areas of future study are indicated.

Circadian Rhythm↗
PubMed2000

A polymorphism in the gene encoding CART is not associated with obesity in Pima Indians.

Cocaine- and amphetamine-regulated transcript (CART) is a hypothalamic peptide that may be involved in the regulation of food intake. We screened the human CART gene and identified a novel C-->G substitution in the 3'-untranslated region of exon 3. This polymorphism was genotyped in a total of 68 Pima Indians with extremes of BMI. The frequencies for alleles C and G were 0.76 and 0.24, respectively. There was no evidence of an association between the genotype frequency at this variant and extremes of BMI in this group of Pima Indians. The results of this study do not suggest a significant role for this variant in exon 3 of CART as a determinant of obesity in Pima Indians.

Adult↗
PubMed2000

Salmonella enterica serovar typhi uses type IVB pili to enter human intestinal epithelial cells.

DNA sequencing upstream of the Salmonella enterica serovar Typhi pilV and rci genes previously identified in the ca. 118-kb major pathogenicity island (X.-L. Zhang, C. Morris, and J. Hackett, Gene 202:139-146, 1997) identified a further 10 pil genes apparently forming a pil operon. The product of the pilS gene, prePilS protein (a putative type IVB structural prepilin) was purified, and an anti-prePilS antiserum was raised in mice. Mutants of serovar Typhi either lacking the whole pil operon or with an insertion mutation in the pilS gene were constructed, as was a strain in which the pilN to pilV genes were driven by the tac promoter. The pil(+) strains synthesized type IVB pili, as judged by (i) visualization in the electron microscope of thin pili in culture supernatants of one such strain and (ii) the presence of PilS protein (smaller than the prePilS protein by removal of the leader peptide) on immunoblotting of material pelleted by high-speed centrifugation of either the culture supernatant or sonicates of pil(+) strains. Control pil mutants did not express the PilS protein. A pilS mutant of serovar Typhi entered human intestinal INT407 cells in culture to levels only 5 to 25% of those of the wild-type strain, and serovar Typhi entry was strongly inhibited by soluble prePilS protein (50% inhibition of entry at 1.4 microM prePilS).

Amino Acid Sequence↗
PubMed2000

Effect of protective agents against cisplatin ototoxicity.

HYPOTHESIS: The goals of this investigation were to compare the efficacy of three protective agents against cisplatin-induced elevation of auditory brainstem response (ABR) thresholds and to examine whether these protective agents prevent cisplatin-induced alterations of the antioxidant defense system in the cochlea of the rat. BACKGROUND: Cisplatin is an ototoxic antitumor agent. Previous animal studies have shown that cisplatin administration causes an elevation of ABR thresholds. These auditory changes are accompanied by alterations in the concentration of glutathione and the antioxidant enzymes in the cochlea. The authors' previous work has indicated that the protective agent diethyldithiocarbamate (DDTC) prevents decrease in glutathione (GSH), alteration of antioxidant enzyme activity, and disruption of cochlear function with cisplatin administration. METHODS: Wistar rats were sedated and underwent pretreatment ABR testing using clicks and tone burst stimuli at 8, 16, and 32 kHz. Control rats received saline by intraperitoneal (i.p.) injection. Positive control rats were administered cisplatin 16 mg/kg i.p. Three groups of rats received protective agents in combination with cisplatin. The DDTC-protected rats were given 600 mg/kg of DDTC subcutaneously 1 hour after cisplatin. Animals protected by 4-methylthiobenzoic acid (MTBA) were given 250 mg/kg of this agent i.p. 30 minutes before cisplatin. Animals protected with ebselen were given 16 mg/kg i.p. one hour before cisplatin. The ABR thresholds were recorded 72 hours after cisplatin administration in all groups. Cochleas were removed, and extracts of the tissues were analyzed for GSH, activities of antioxidant enzymes (superoxide dismutase [SOD], catalase, glutathione peroxidase, and glutathione reductase) and malondialdehyde (MDA) (as an index of lipid peroxidation). RESULTS: Cisplatin-treated rats had significant ABR threshold shifts, ranging from 27 to 40 dB. Rats administered each of the three protective agents in combination with cisplatin had ABR threshold shifts of <10 dB. The cochleae of rats administered cisplatin alone had nearly a 50% depletion of glutathione and about a 50% reduction in the activities of SOD, glutathione peroxidase, and glutathione reductase, while catalase activity was reduced to 70% of control values. These changes were accompanied by a reciprocal elevation of MDA of 165%. These changes, namely, the depletion of GSH and antioxidant enzyme activity and the elevation of MDA in the cochlea, were largely attenuated by the administration of the protective agents tested. CONCLUSION: These findings suggest that cisplatin ototoxicity is related to lipid peroxidation and that the use of protective agents prevents hearing loss and lipid peroxidation by sparing the antioxidant system in the cochlea. These results suggest the possibility that the clinical use of protective agents could effectively reduce or prevent damage to the inner ear of patients receiving cisplatin chemotherapy, provided that the antitumor effect is not altered.

Adjuvants, Immunologic↗
PubMed1999

Risk for Alzheimer's disease in older late-onset cases is associated with HLA-DRB1*03.

The allele frequency of the HLA-DRB1 gene was compared between groups of 48 clinically diagnosed elderly Alzheimer's disease (AD) cases and 44 pathologically confirmed elderly control cases. Specific primers were used to PCR amplify the highly polymorphic second exon of HLA-DRB1 using DNA extracted from blood samples or frozen brain tissue. The allele type was identified using sequence specific oligonucleotide probes. The results showed an increased frequency of DRB1*03 (P < 0.006) and decreased frequency of DRB1*09 (P < 0.049) in the AD cases compared with the controls. The results suggest that DRB1*03 is associated with an increased risk and DRB1*09 a possible decreased risk for the development of late-onset AD with first detectable clinical symptoms occurring at age 75 years or greater.

Age of Onset↗
PubMed1999

Reducing the risk of major elective surgery: randomised controlled trial of preoperative optimisation of oxygen delivery.

OBJECTIVES: To determine whether preoperative optimisation of oxygen delivery improves outcome after major elective surgery, and to determine whether the inotropes, adrenaline and dopexamine, used to enhance oxygen delivery influence outcome. DESIGN: Randomised controlled trial with double blinding between inotrope groups. SETTING: York District Hospital, England. SUBJECTS: 138 patients undergoing major elective surgery who were at risk of developing postoperative complications either because of the surgery or the presence of coexistent medical conditions. INTERVENTIONS: Patients were randomised into three groups. Two groups received invasive haemodynamic monitoring, fluid, and either adrenaline or dopexamine to increase oxygen delivery. Inotropic support was continued during surgery and for at least 12 hours afterwards. The third group (control) received routine perioperative care. MAIN OUTCOME MEASURES: Hospital mortality and morbidity. RESULTS: Overall, 3/92 (3%) preoptimised patients died compared with 8/46 controls (17%) (P=0.007). There were no differences in mortality between the treatment groups, but 14/46 (30%) patients in the dopexamine group developed complications compared with 24/46 (52%) patients in the adrenaline group (difference 22%, 95% confidence interval 2% to 41%) and 28 patients (61%) in the control group (31%, 11% to 50%). The use of dopexamine was associated with a decreased length of stay in hospital. CONCLUSION: Routine preoperative optimisation of patients undergoing major elective surgery would be a significant and cost effective improvement in perioperative care.

Aged↗
PubMed1999

Frequency of HLA-A and B alleles in early and late-onset Alzheimer's disease.

The frequency of various allele types of the class I Major Histocompatibility Complex (MHC) genes HLA-A and HLA-B were compared between pathologically confirmed groups of late and early-onset Alzheimer's disease (AD) and a control group. DNA was extracted from frozen brain tissue and the highly polymorphic second and third exons of the HLA-A and HLA-B genes were independently PCR amplified using specific primers. Individual allele types were identified using sequence-specific oligonucleotide probes. The results showed that the main frequency differences occurred between the late-onset AD and the control group however none of these reached statistical significance.

Adult↗