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D Kelly

Publications and source records attributed to D Kelly.

At least 127 records · Page 7Linked to original sources
PubMed1994

The induction of des-Arg9-bradykinin-mediated hyperalgesia in the rat by inflammatory stimuli.

1. The B1 receptor agonist des-Arg9-BK does not induce mechanical hyperalgesia when injected into the rat knee joint at 1-100 nmol, or thermal hyperalgesia when injected intravenously up to 1 mumol/kg. 2. Bradykinin (BK), administered into the joint, (1 nmol-1 mumol) induces a mechanical hyperalgesia, which is maximal by 4 h. Co-administration of BK with Hoe 140 (5 pmol) blocked development of the hyperalgesia, whereas des-Arg9-Leu8-BK (0.5 nmol) had no effect. Intravenous BK had no effect on thermal paw withdrawal latencies up to 1 mumol/kg. 3. Following joint inflammation induced by local Freund's complete adjuvant, intraarticular injection of des-Arg9-BK (0.05-10 nmol) and BK (0.5-100 nmol) caused a reduction in tolerated load. Co-administration of des-Arg9-Leu8-BK (0.5 nmol) with des-Arg9-BK (0.5 nmol) blocked development of the hyperalgesia, whereas Hoe 140 (5 pmol) had no effect. BK (1 nmol)-induced hyperalgesia was blocked by Hoe 140 but not des-Arg9-Leu8-BK. 4. Following UV irradiation of the paw, intravenous des-Arg9-BK and BK reduced paw withdrawal latencies to a noxious thermal stimulus indicating thermal hyperalgesia. The latency reduction induced by des-Arg9-BK and BK was prevented with co-administration of des-Arg9-Leu8-BK 200 nmol/kg, but not with Hoe 140 0.5 mumol/kg. 5. After interleukin-1 beta pre-treatment (1 unit into the joint or paw) des-Arg9-BK induced both thermal and mechanical hyperalgesia. Co-administration of des-Arg9-Leu8-BK 0.5 nmol with des-Arg9-BK 0.5 nmol into the joint prevented development of hyperalgesia and co-administration of des-Arg9-Leu8-BK (200 nmol/kg, iv) with des-Arg9-BK 10 nmol/kg prevented reduction of thermal withdrawal latencies. 6. These data suggest that after an inflammatory insult B1 receptors may play a role in the transduction of nociceptive information.

Animals↗
PubMed1994

A missense mutation in the beta myosin heavy chain gene is a predictor of premature sudden death in patients with hypertrophic cardiomyopathy.

BACKGROUND: Familial hypertrophic cardiomyopathy (FHCM) is an autosomal dominant disease with protean clinical manifestations, ranging from asymptomatic to that of severe heart failure or sudden death. There is no known parameter in individuals with hypertrophic cardiomyopathy (HCM) that predicts a specific clinical event. This is particularly troublesome for premature sudden death that frequently occurs in young athletes without prior symptoms. Recent identification of mutations in the beta myosin heavy chain (beta MHC) gene that co-segregate with the inheritance of the disease provides an opportunity to determine whether certain mutations are more likely to induce a particular clinical event. In this study we analyzed the genotype and phenotype of individuals from two unrelated families with HCM in which the affected individuals have the same missense mutation in exon 13 (G1208A) of the coding sequence for beta MHC. METHODS: Individuals from two unrelated families with the diagnosis of FHCM were screened by history, physical examination, electrocardiography, and two dimensional echocardiography. After extraction of DNA from the blood of these individuals, the exon 13 of the beta MHC gene was amplified by polymerase chain reaction (PCR), and the PCR product was digested with Ddel restriction endonuclease. The digestion products were separated by gel electrophoresis and identified by ethidium bromide staining. RESULTS: We studied 54 individuals from the two families, 21 were affected with HCM of which eleven died prematurely, eight from sudden cardiac death. While most of the nine affected individuals studied had septal hypertrophy, three had concentric hypertrophy and six, left ventricular outflow tract obstruction. Onset of symptoms was in the second decade of life. Electrophoretic separation of the digested DNA (exon 13) from unaffected individuals provided two fragments of 84 and 70 bp in size, as expected. In contrast, DNA from individuals affected with HCM showed four fragments of 84 bp, 70 bp, 52 bp and 32 bp indicating they inherited the mutation. In only one 10 year old male was the mutation present without evidence of HCM which gives an overall penetrance of 86%. CONCLUSIONS: The missense mutation in exon 13 of the beta MHC gene in individuals with FHCM is associated with high penetrance, highly variable expressivity, severe disease, early in onset and a high incidence of premature sudden death. Based on these results we recommend individuals from families with HCM be screened for this missense mutation and if positive, be counselled to avoid combative sports, as it is these activities that often precipitate sudden death.

Adult↗
PubMed1994

PAPNET analysis of reportedly negative smears preceding the diagnosis of a high-grade squamous intraepithelial lesion or carcinoma.

One hundred fourteen cervical smears obtained from 18 women developing biopsy-proven high-grade squamous intraepithelial lesions and two with invasive squamous carcinomas were analyzed by two pathologists using the PAPNET neural network-based automated screening system (PAPNET Analyses A and B). The smears were originally reported as negative and had been previously rescreened and reclassified according to The Bethesda System. Using the PAPNET video displays of 128 potentially abnormal cellular images per smear, each reviewer (PAPNET A and B) determined whether a smear required conventional rescreening. Results of the PAPNET triage were compared with the reclassification diagnoses of the smears by conventional microscopy. PAPNET Analysis A selected eight (14%) smears reclassified as negative, 25 (69%) as atypical squamous cells of undetermined significance, and 15 (71%) as squamous intraepithelial lesions (SIL) for rescreening. In PAPNET Analysis A, two (10%) SILs were not selected for rescreening, and four (19%) were considered unsatisfactory for analysis. PAPNET Analysis B selected 21 (37%) smears reclassified as negative, 25 (69%) as atypical squamous cells of undetermined significance, and 18 (86%) as SIL for review. In PAPNET Analysis B, two (10%) SILs were missed, and one (5%) smear was unsatisfactory for analysis. Each PAPNET analysis selected smears for rescreening in 19 (95%) of 20 patients and detected SILs in 10 patients that were missed in the original screening. Using PAPNET, SILs would have been detected a median of 56 months (PAPNET A) and 62 months (PAPNET B) before their actual discovery. These preliminary data suggest that PAPNET may help detect SILs missed in routine cytologic screening.(ABSTRACT TRUNCATED AT 250 WORDS)

Carcinoma, Squamous Cell↗
PubMed1993

Confirmation that the velo-cardio-facial syndrome is associated with haplo-insufficiency of genes at chromosome 22q11.

The velo-cardio-facial syndrome (VCFS) and DiGeorge sequence (DGS) have many similar phenotypic characteristics, suggesting that in some cases they share a common cause. DGS is known to be associated with monosomy for a region of chromosome 22q11, and DNA probes have been shown to detect these deletions even in patients with apparently normal chromosomes. Twelve patients with VCFS were examined and monosomy for a region of 22q11 was found in all patients. The DNA probes used in this study could not distinguish the VCFS locus and the DGS locus, indicating that the genes involved in these haploinsufficiencies are closely linked, and may be identical. The phenotypic variation of expression in VCFS and DGS may indicate that patients without the full spectrum of VCFS abnormalities but with some manifestations of the disorder may also have 22q11 deletions.

Abnormalities, Multiple↗
PubMed1993

Liver transplantation in babies and children with extrahepatic biliary atresia.

Orthotopic liver transplantation (OLT) is a life-saving procedure for end-stage liver failure. We reviewed 39 children (24 girls, 15 boys) who received OLT for biliary atresia from 1987 to 1991. Twenty had unsuccessful portoenterostomy, 6 were referred too late for a drainage operation, and the remaining 13 achieved bile drainage but developed portal hypertension. At transplant 37 had decompensated liver disease with varices (28), ascites (24), encephalopathy (17), and gastrointestinal bleeding (12). The median weight and age at transplant were 8 kg and 12.6 months, respectively. The median waiting time was 65 days. Forty-eight grafts (30 reduced and 18 whole) were performed; graft loss was 33% and 27%, respectively. Of the 30 segmental grafts, 15 were reduced conserving the left lateral segment and hepatic vein (Brisbane technique)--13 were from the left lobe and 2 from the right lobe. The overall subject survival rate is 72%. Eleven deaths occurred: primary nonfunction (3), sepsis (3), perioperative bleed (3), and other causes (2). Early complications included: hepatic artery thrombosis (5), hepatic vein thrombosis (2), bowel perforation (3), biliary leak (3), and acute rejection (8). Later complications were chronic rejection (4) and biliary stricture requiring reconstruction (3). Follow-up at 12 months confirms good quality of life for both child and family with catch up growth and normal development. Technical advances in reduction hepatectomy have allowed us to treat small babies under 1 year with an urgent requirement for OLT, with comparable results to those obtained with whole grafts. In conclusion, in the future size and age need not be a contraindication to OLT in children with biliary atresia.

Biliary Atresia↗
PubMed1993

Induction of bradykinin B1 receptors in vivo in a model of ultra-violet irradiation-induced thermal hyperalgesia in the rat.

1. The role of bradykinin B1 receptors in the thermal hyperalgesia following unilateral ultra-violet (u.v.) irradiation of the hindpaw of rats has been investigated. 2. In non-irradiated (naive) animals the B1 receptor agonist des-Arg9-bradykinin and bradykinin (BK) (up to 1 mumol kg-1 i.v.) had no effect on withdrawal latency to a noxious heat stimulus when administered 60 min before testing. 3. Following exposure of one hindpaw to strong u.v. irradiation the withdrawal latency of the u.v.-treated paw to radiant noxious heat fell by a maximum of 50% after 48 h. There was no reduction in latency in the contralateral paw. 4. des-Arg9-BK (1-100 nmol kg-1 i.v.) administered 24 h after u.v. exposure caused a further dose-dependent fall (50 +/- 4% reduction from saline injected animals at 100 nmol kg-1 i.v.) in withdrawal latency in the u.v.-treated paw when measured 60 min after injection. The withdrawal latency of the contralateral paw was also reduced but to a lesser extent following des-Arg9-BK (100 nmol kg-1 i.v.) with a maximum reduction of 19 +/- 3%. 5. Bradykinin also induced a further reduction in withdrawal latency (33 +/- 5% reduction at 1 mumol kg-1) although it was not as effective as des-Arg9-BK. Bradykinin did not reduce the withdrawal latency in the contralateral paw. 6. The hyperalgesic action of both des-Arg9-BK (10 nmol kg-1 i.v.) and bradykinin (100 nmol kg-1 i.v.)were antagonized by the B, receptor antagonist, des-Arg9,Leu8-BK (200 nmol kg-1 i.v.) but not by the B2 receptor antagonist, HOE 140 (0.5 .micromol kg-1 i.v.).7. The results suggest that in conditions of inflammatory hyperalgesia bradykinin B1 receptors are induced both locally and distant to the inflamed area, activation of which leads to further thermal hyperalgesia. In addition, in these conditions bradykinin appears to act predominantly via B1 receptors,presumably after degradation to des-Arg9-BK.

Animals↗
PubMed1993

Noonan's and DiGeorge syndromes with monosomy 22q11.

A boy with the dysmorphic features of Noonan's syndrome and pulmonary valve stenosis who had evidence of hypoparathyroidism and abnormal T lymphocyte numbers in the neonatal period is reported. He had a normal karyotype but molecular analysis revealed a submicroscopic deletion within chromosome 22q11, the region deleted in DiGeorge syndrome. Thus this child has both Noonan's syndrome and DiGeorge syndrome; 22q11 is a candidate region for a gene defective in Noonan's syndrome.

Blotting, Southern↗
PubMed1993

Effect of preclosure colostrum intake on the development of the intestinal epithelium of artificially reared piglets.

Trophic factors in mammalian colostrum promote the growth of the small intestine of neonates. To investigate the effect of colostrum feeding on the expression of specific intestinal proteins, animals were reared in a minimal disease unit and fed either sow colostrum or a commercial substitute by gastric intubation at 3-hour intervals over the first 24 h of life. Animals were then reared on a commercial milk replacer and fed over a maximum period of 5 weeks. Intestinal protein, DNA and histology data suggested a positive effect of colostrum on intestinal growth in the initial postnatal period. At week 1 post partum intestinal lactase was found to decline significantly in colostrum-fed (CF) piglets compared to substitute-fed animals. This effect was no longer apparent at 3 and 5 weeks post partum. Sucrase activity was significantly greater in CF piglets and this effect was sustained during the 5 postpartum weeks studied. The changes in enzyme activity could be correlated with posttranslational sialylation of intestinal membranes. These result suggest that feeding colostrum enhances the maturational decline in lactase activity and the expression of sucrase activity. The role of glycosylation of enzyme proteins in relation to their biological activity is discussed.

Animal Feed↗
PubMed1993

The challenge of attention deficit disorder in children who are deaf or hard of hearing.

Attention Deficit Disorder is a common cause of school problems. Yet, the condition has not been examined extensively in children who are deaf or hard of hearing. In this article, the varying manifestations and subgroups of the condition and its impact on the behavior and performance of these children are discussed. Its prevalence is examined by a review of the literature and an analysis of studies at a state residential school for the deaf. In this population, the prevalence appears to be similar to that reported in hearing children; however, some subgroups of deaf children, such as those with acquired hearing loss, are at greater risk. Recent legislative initiatives concerning the condition are discussed, as are challenges for managing the problem and directions for future research.

Adolescent↗
PubMed1993

Evaluating and managing attention deficit disorder in children who are deaf or hard of hearing.

Effective management of children who are deaf or hard of hearing and faced with the added challenge of Attention Deficit Disorder requires a comprehensive and coordinated spectrum of services. A complex array of underlying or associated factors can mimic, cause, or exaggerate the symptoms. Careful diagnosis is thus essential and is the prerequisite for developing effective intervention. In this article, we present a practical approach to the problem, based on experience with a model treatment program at a residential school for the deaf. Suggestions are provided regarding the diagnostic work-up of children presenting with attention problems. Management approaches are discussed for the classroom, home, and residential area as well as specialized therapeutic intervention and the use of medication. A model for implementing a treatment program in a school is presented, and future challenges are discussed.

Achievement↗
PubMed1992

Velo-cardio-facial syndrome associated with chromosome 22 deletions encompassing the DiGeorge locus.

The large clinical overlap between DiGeorge syndrome and velo-cardio-facial syndrome suggests an aetiological connection. DiGeorge syndrome is associated with microdeletions of chromosome 22q11 and is therefore likely to be caused by reduced dosage of genes within this region. We present preliminary data that velocardiofacial syndrome patients have similar chromosome deletions, a finding consistent with the hypothesis that these disorders represent part of a spectrum of abnormalities seen with monosomy for 22q11.

Abnormalities, Multiple↗
PubMed1992

Expression of the neu oncogene under the transcriptional control of the myelin basic protein gene in transgenic mice: generation of transformed glial cells.

We have taken a transgenic approach in an effort to specifically transform oligodendrocytes, the myelinating glial cells of the central nervous system (CNS). Transgenic mice were generated with a DNA construct that contained the activated neu oncogene under the transcriptional control of the myelin basic protein (MBP) gene. The MBP/c-neu transgenic animals have experienced a low incidence of brain tumors that express molecular markers specific to oligodendrocytes, providing a mouse model to study the formation and progression of oligodendrocyte tumors. A tumor from a transgenic animal has been dispersed in culture, and transformed cells that express properties of oligodendrocytes and astrocytes have been maintained. The degree to which these cells express phenotypic characteristic of oligodendrocytes or astrocytes is influenced by culture conditions. These transformed cells should serve as a valuable resource with which to study various molecular and biochemical aspects of the myelination process, as well as the lineage interrelationship of CNS glial cells.

Animals↗
PubMed1992

Induced reciprocal translocation in transgenic mice near sites of transgene integration.

Transgenic mice (JCP0 #18), heterozygous for an insertion of approximately 50 copies of the rat peripheral myelin (P0) protein cDNA, displayed a pattern of reduced litter size that suggested a chromosome rearrangement. Chromosome banding studies of fetal cells disclosed the presence of an apparently balanced translocation between a Chromosome (Chr) 1 and 14 with breakpoints at bands 1H3 and 14C3. In situ hybridization of biotin-labeled P0 rat cDNA probe to chromosome spreads and detection of specific signal with fluorescein isothiocyanate-conjugated avidin revealed a strong signal on the 1(14) translocation chromosome at the site of the breakpoint. A weaker signal was present near the breakpoint on the 14(1) derivative chromosome. These results suggest an etiologic relationship between the insertion of the transgene and the origin of the translocation. To further elucidate possible mechanisms, we first mapped the endogenous P0 gene (gene symbol Mpp). As previously reported (You et al., Genomics 9: 751, 1991), we found that Mpp is located on Chr 1 in the region of the translocation breakpoint in JCP0 mice. Subsequently, we have carried out pulsed-field gel and standard Southern analyses with P0 gene probes, but found no evidence for a direct involvement of the endogenous P0 gene in the process that generated the balanced reciprocal translocation. Thus, we favor the hypothesis that, during repair of DNA strand breakage--possibly induced by the microinjection procedure--the transgene copies were ligated to broken ends of Chrs 1 and 14. According to convention, this translocation is designated T(1;14)1Po. Homozygotes are phenotypically normal and breed well; they will be useful for genetic and physical mapping of Chrs 1 and 14.

Animals↗
PubMed1992

Transcriptional regulation of the murine k-FGF gene in embryonic cell lines.

Previous studies have shown that embryonal carcinoma (EC) cells express the fibroblast growth factor k-FGF; however, there is a large decrease in the expression of this gene when EC cells differentiate. In addition, it has been shown that differentiation of mouse F9 EC cells reduces the expression of a reporter gene under the control of both the putative human k-FGF promoter and an enhancer-like element that is located in the third exon of the k-FGF gene. Given the low degree of sequence similarity between the human k-FGF gene and the murine k-FGF gene upstream of the transcription start site, it was unclear whether human sequences mimic fully the regulation of the k-FGF gene in mouse cells. To address this question, we have examined the expression of gene constructs containing various regions of the murine k-FGF gene in two mouse EC cell lines and one mouse embryonic stem (ES) cell line. Our results demonstrate that the mouse 5' flanking region, like the human 5' flanking region, cannot support expression of the reporter gene. In both EC cell lines and the ES cell line, expression of the reporter gene is elevated 10- to 100-fold by the addition of a 316-bp region taken from the third exon of the murine k-FGF gene. In addition, we provide evidence that octamer binding proteins are involved in the regulation of the k-FGF gene. Last, this study has identified regions upstream of the transcription start site that appear to regulate the expression of the murine k-FGF gene in EC cells and in ES cells.

Animals↗
PubMed1992

Differential regulation of the transforming growth factor type-beta 2 gene promoter in embryonal carcinoma cells and their differentiated cells.

Previous studies have shown that EC cells do not express detectable levels of TGF-beta 2 or its mRNA until they differentiate. This suggested that differentiation influences the transcription of the TGF-beta 2 gene in this model system. To address this possibility, we have examined the activity of the TGF-beta 2 promoter in EC cells and their differentiated cells using gene constructs containing various portions of the TGF-beta 2 promoter inserted upstream of the reporter gene, chloramphenicol acetyltransferase (CAT). We determined that the level of CAT increases approximately ninefold when EC cells were induced to differentiate. Our studies also indicate that the TGF-beta 2 promoter contains at least two positive regulatory elements that are separated by a negative regulatory element. Finally, we have identified a CRE/ATF-like site that appears to be responsible for a positive regulatory element located between -77 and -40.

Base Sequence↗
PubMed1992

Thyroid-specific and hormone-dependent expression of rat thyroglobulin promoter fused with bacterial chloramphenicol acetyltransferase gene in transgenic mice.

The minimal promoter of rat thyroglobulin (TG) gene (168 bp) was fused with bacterial chloramphenicol acetyltransferase (CAT) gene, and transgenic mice carrying the TGCAT gene were produced. The minimal promoter is sufficient for thyroid-specific and hormone-dependent expression of TGCAT in transgenic mice. Deletion of a region between -128 and -92 bp (TGII), which is not required for the expression of TGCAT in transient expression assays but whose sequence is most extensively conserved among different species, appears to decrease frequency of the expression of TGCAT in transgenic mice. However, the same deletion apparently has no significant effect on TG promoter activity in stably transformed rat FRTL-5 cells.

Animals↗