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Biomedical subjects

J Hughes

Publications and source records attributed to J Hughes.

At least 271 records · Page 15Linked to original sources
PubMed1995

The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains.

Characterization of the polycystic kidney disease 1 (PKD1) gene has been complicated by genomic rearrangements on chromosome 16. We have used an exon linking strategy, taking RNA from a cell line containing PKD1 but not the duplicate loci, to clone a cDNA contig of the entire transcript. The transcript consists of 14,148 bp (including a correction to the previously described C terminus), distributed among 46 exons spanning 52 kb. The predicted PKD1 protein, polycystin, is a glycoprotein with multiple transmembrane domains and a cytoplasmic C-tail. The N-terminal extracellular region of over 2,500 aa contains leucine-rich repeats, a C-type lectin, 16 immunoglobulin-like repeats and four type III fibronectin-related domains. Our results indicate that polycystin is an integral membrane protein involved in cell-cell/matrix interactions.

Amino Acid Sequence↗
PubMed1995

Integrated maps of the chromosomes in Dictyostelium discoideum.

Detailed maps of the six chromosomes that carry the genes of Dictyostelium discoideum were constructed by correlating physically mapped regions with parasexually determined linkage groups. Chromosomally assigned regions were ordered and positioned by the pattern of altered fragment sizes seen in a set of restriction enzyme mediated integration-restriction fragment length polymorphism (REMI-RFLP) strains each harboring an inserted plasmid that carries sites recognized by NotI, SstI, SmaI, BglI and ApaI. These restriction enzymes were used to digest high molecular weight DNA prepared from more than 100 REMI-RFLP strains and the resulting fragments were separated and sized by pulsed-field gels. More than 150 gene probes were hybridized to blots of these gels and used to map the insertion sites relative to flanking restriction sites. In this way, we have been able to restriction map the 35 mb genome as well as determine the map position of more than 150 genes to with approximately 40 kb resolution. These maps provide a framework for subsequent refinement.

Animals↗
PubMed1995

Autosomal dominant polycystic kidney disease: molecular analysis.

Using a positional cloning approach the major autosomal dominant polycystic kidney disease (ADPKD) gene (PKD1) has been identified on chromosome 16: a disease associated chromosome translocation was instrumental in its identification. Study of the PKD1 gene has been complicated because most of the gene lies in a genomic region reiterated elsewhere on the same chromosome. The duplicate area contains three genes which share substantial homology with PKD1 and generate polyadenylated transcripts. Most PKD1 mutations have so far been detected in the single copy, 3' end of the gene, but a group of patients with deletion of PKD1 and the adjacent TSC2 gene, which have severe infantile polycystic kidney disease, have also been characterised. The full length transcript of PKD1 (approximately 14 kb) has now been cloned and is predicted to encode a protein, polycystin, of 4302/3 aa. Polycystin contains multiple extracellular domains including leucine rich repeats, a C-type lectin, immunoglobulin and fibronectin type III-like domains and has a C terminal region which is likely associated with the membrane. These homologies indicate that polycystin is a cell-cell/matrix interaction protein.

Base Sequence↗
PubMed1995

I-123 MIBG scintigraphy in adults. A report of clinical experience.

Thirty-one adult patients with clinical findings suggestive of pheochromocytoma were studied with I-123 MIBG. All patients had images obtained at 24 and 48 hours. Five patients had abnormal uptake proved to be because of I-123 MIBG avid tumors. The remaining 26 patients had no proven tumors and showed physiologic uptake in various organs. The 24-hour images were of high quality. In all cases, the 48-hour images contributed no significant additional information. Only in 1 patient did the 48-hour image add some certainty. Physiologic uptake was seen in the salivary glands, liver, G.I. tract, and urinary bladder in all patients (100%). Uptake was also observed in the lung and heart (90%), normal adrenal glands (32%), thyroid (29%), spleen (23%) uterus (13%), and neck muscles (6%). The authors' experience indicates that I-123 MIBG gives superior images compared to the previously used I-131 MIBG, that the optimum imaging time for adults is 18-24 hours, and that normal distribution patterns including uterine and neck muscle uptake should be familiar to physicians interpreting the studies.

3-Iodobenzylguanidine↗
PubMed1995

Reducing polypharmacy in extended care.

In this 5-year prospective study, we determined the feasibility of reducing polypharmacy in a long-term care institution by a systematic review of the pharmacy records. At 6-month intervals, the computer printout of all medications prescribed to patients in a 550-bed institution was reviewed. After patients taking more than 10 different drugs were identified, their physician was notified and was asked to review their medications according to specific guidelines. The number of patients taking 10 or more medications was reduced from 67, when the program was started, to 9. The average number of medications per patient was reduced from 5.5 to 4.6. This program reduced the prevalence of polypharmacy and had long-lasting effects on the physicians' prescribing habits. We also believe it led to improved patient care by reducing the potential for drug interactions and to cost savings for the pharmacy.

Aged↗
PubMed1995

Adverse drug reactions in a paediatric intensive care unit.

Adverse drug reactions (ADRs) were prospectively studied in critically ill infants and children. Seventy-six ADRs were reported in 63 patients out of a study group of 899 patients. The majority of the ADRs were mild (49), although 19 were of moderate severity and 8 were severe. Thirty-five ADRs required treatment or alteration in treatment. Midazolam, morphine, salbutamol, vecuronium, hydrocortisone and theophylline were the drugs most likely to cause an ADR. One-third of the ADRs were due to drugs used outside their product licence. The majority of the ADRs were reported by nurses (36) and pharmacists (30). We believe that it is possible to prospectively study drug toxicity in critically ill infants and children.

Adolescent↗
PubMed1995

Ultimate justification: Wittgenstein and medical ethics.

Decisions must be justified. In medical ethics various grounds are given to justify decisions, but ultimate justification seems illusory and little considered. The philosopher Wittgenstein discusses the problem of ultimate justification in the context of general philosophy. His comments, nevertheless, are pertinent to ethics. From a discussion of Wittgensteinian notions, such as 'bedrock', the idea that 'ultimate' justification is grounded in human nature as such is derived. This discussion is relevant to medical ethics in at least five ways: it shows generally what type of certainty there is in practical ethics; it seems to imply some objective foundation to our ethical judgements; it squares with our experience of making ethical decisions; it shows something of the nature of moral arguments; and, finally, it has implications for teaching medicine and ethics.

Ethical Analysis↗
PubMed1995

Study of Alzheimer's dementia patients with parkinsonian features.

This paper presents a study to test the hypothesis that a parkinsonian subtype of Alzheimer's disease exists. Twenty-one patients with dementia of the Alzheimer's type (DAT) and coexistent parkinsonian features were matched to 21 DAT control patients without parkinsonian signs. All subjects were drawn from 136 patients with DAT evaluated between 1980 and 1982. Items from a standardized clinical evaluation at the time of diagnosis, from continuous yearly follow-ups, and neuropathologic examination were compared to determine if qualitative differences exist between the two groups. Those with parkinsonian features had significantly shorter duration of symptoms prior to presentation, a trend toward more reports of decreased self-care, and more primitive reflexes on physical examination. While the total Folstein Mini-Mental State Exam (MMSE) scores at presentation were not significantly different, the cases showed greater impairment in language and registration subitems. During follow-up, no differences were observed in performance on MMSE and Dementia Rating Scale scores. Survival curves showed a trend toward poorer survival in the cases. Neuropathologic data were obtained on seven patients with both DAT and parkinsonian features and showed three cases with Alzheimer's disease (AD) alone and four with AD and Parkinson's disease. Four of the DAT control patients were examined neuropathologically, and all had AD without evidence of Parkinson's disease. The results provide preliminary evidence that Alzheimer's patients with parkinsonian signs are a subtype characterized by distinct neurologic signs and a more rapid course.

Aged↗
PubMed1995

Polycystic kidney disease. 1: Identification and analysis of the primary defect.

The identification of the primary defect in autosomal dominant polycystic kidney disease (ADPKD) by biochemical methods has proved difficult because of the complexity of the cystic kidney. However, by the use of the genetic method of positional cloning, a gene accounting for approximately 85% of ADPKD, PKD1, has now been identified in the chromosome region 16p13.3. Its exact location was pinpointed because it was bisected by a chromosome translocation; members with the balanced exchange had PKD1. The PKD1 gene encodes an approximately 14-kb transcript, but full characterization was complicated, because most of the gene lies in a genomic region that is duplicated elsewhere on chromosome 16; the duplicate area encodes three genes with substantial homology to PKD1. At present, only seven mutations of PKD1 have been characterized and these are clustered in the nonduplicated, 3' end of the gene. However, a number of patients with large deletions of the PKD1 and adjacent tuberous sclerosis 2 (TSC2) genes, who have tuberous sclerosis and severe childhood-onset polycystic kidney disease, have also been described. Recently, the entire sequence of the PKD1 transcript and the genomic region containing the gene have been determined. The PKD1 gene covers approximately 52 kb of genomic DNA and is divided into 46 exons. The transcript is approximately 14.15 kb, and the predicted protein polycystin is 4302/3 amino acids with a calculated mass of approximately 460 kd. Polycystin contains several distinctive extracellular domains, including a flank-leucine rich repeat-flank domain, a C-type lectin, 16 approximately 85-amino-acid units that are similar to immunoglobulin repeats, four fibronectin Type III-related domains, and a low-density lipoprotein A domain. The C-terminal third of the protein has multiple hydrophobic regions, and modeling of this region suggests the presence of many transmembrane domains and a cytoplasmic C terminus. Hence, polycystin is probably an integral membrane protein with multiple extracellular domains that are involved in cell-cell and/or cell-matrix interactions. The ADPKD phenotype suggests that polycystin may play a role in cell-matrix communication, which is important for normal basement membrane production and for controlling cellular differentiation.

Chromosome Mapping↗
PubMed1995

Comparison of tissues adjacent to different mechanical stress areas from patients with clinically failed implants.

Implants consisting of metallic and polymeric components are used to treat musculoskeletal diseases. At revision surgery, significant wear products maybe recovered from tissues adjacent to failed implants. The failing implant is clinically associated with pain, and radiographic analysis demonstrates deterioration of the bone surrounding the implant. There is concern that areas of high contact stresses and articulating surfaces lead to the generation of wear particles that trigger a biological response that mediates the lysis of bone. This study compares the tissues retrieved from various areas exposed to different mechanical stresses. Tissues were processed for biochemical and immunohistochemical factors (cytokines) responsible for bone resorption. The results from this study showed by both quantitative enzyme linked immunoassay and qualitatively by immunohistology a marked increase in cytokines, interleukin-1 and tumor necrosis factor, in areas of articulation compared to other areas. Evaluation of tissues histochemically demonstrated the presence of fibroblast, macrophages, and multinucleated giant cells. Overall, the results indicate that the generation of wear particles lead to the production of biological mediators responsible for the failure of the implants.

Hip Prosthesis↗
PubMed1995

Perfusion and ventilation scans in patients with extensive obstructive airway disease: utility of single-breath (washin) xenon-133.

UNLABELLED: The presence of extensive obstructive airway disease in many patients leads to an interpretation of intermediate or indeterminate probability for pulmonary emboli using ventilation/perfusion lung scans. We observed that patients with extensive obstructive airway disease having perfusion abnormalities matching those on a single-breath xenon image usually have a normal pulmonary angiogram. This study's objective was to further assess the utility of a single-breath image in evaluating patients with extensive obstructive airway disease and abnormal perfusion studies categorized as having intermediate or indeterminate probability of pulmonary embolism in an attempt to decrease the number of nondiagnostic studies. METHODS: We studied retrospectively 33 patients with extensive obstructive airway disease, with abnormal perfusion scans and no infiltrates on chest x-ray categorized as having intermediate or indeterminate probability of pulmonary embolism. We established the presence or absence of matching ventilation and perfusion abnormalities by comparing perfusion scan and single-breath images. RESULTS: Among 25 patients with perfusion abnormalities matching the initial ventilation pattern on single-breath images, only 1 (4%) had pulmonary emboli as documented by pulmonary angiogram. Four out of the remaining 8 patients with no matching perfusion and single-breath ventilation pattern had pulmonary emboli (50%). CONCLUSION: Patients categorized by ventilation/perfusion scintigraphy as having intermediate or indeterminate probability for pulmonary emboli due to the presence of extensive obstructive airway disease can be further subclassified using single-breath images. Patients with matching perfusion and single-breath ventilation pattern should be categorized as having low probability for pulmonary embolism, regardless of the extent of the ventilation abnormalities.

Administration, Inhalation↗
PubMed1994

Modulation of striatal aspartate and dynorphin B release by cholecystokinin (CCK-8) studied in vivo with microdialysis.

Sulphated cholecystokinin-8 (CCK-8) given into the neostriatum of the rat by in vivo microdialysis produced a concentration-dependent (1-100 microM) increase in extracellular aspartate (Asp) and dynorphin B (Dyn B), but not in glutamate, GABA or dopamine levels. The increase in Asp levels produced by 10 microM CCK-8 was approximately 10 fold and was inhibited (approximately 50%) by the CCKB antagonist L-365,260 (20 mg kg-1, i.p.), while the increase in Dyn B (approximately 2 fold) was totally abolished. Both increases were inhibited (approximately 50%) by local infusion of 10 microM of tetrodotoxin (TTX). Thus, CCK exerts modulatory effects in the basal ganglia, possibly by interacting with local neostriatal neurones releasing Asp, and with Dyn B-containing neurones projecting to the pars reticulata of the substantia nigra.

Animals↗
PubMed1994

Immunity to malaria elicited by hybrid hepatitis B virus core particles carrying circumsporozoite protein epitopes.

The hepatitis B virus (HBV) nucleocapsid antigen (HBcAg) was investigated as a carrier moiety for the immunodominant circumsporozoite (CS) protein repeat epitopes of Plasmodium falciparum and the rodent malaria agent P. berghei. For this purpose hybrid genes coding for [NANP]4 (C75CS2) or [DP4NPN]2 (C75CS1) as internal inserts in HBcAg (between amino acids 75 and 81) were constructed and expressed in recombinant Salmonella typhimurium. The resulting hybrid HBcAg-CS polypeptides purified from S. typhimurium were particulate and displayed CS and HBc antigenicity, however, the HBc antigenicity was reduced compared to native recombinant HBcAg. Immunization of several mouse strains with HBcAg-CS1 and HBcAg-CS2 particles resulted in high titer, P.berghei- or P.falciparum-specific anti-CS antibodies representing all murine immunoglobulin G isotypes. The possible influence of carrier-specific immunosuppression was examined, and preexisting immunity to HBcAg did not significantly affect the immunogenicity of the CS epitopes within HBcAg-CS1 particles. Similarly, the choice of adjuvant did not significantly alter the immunogenicity of HBcAg-CS hybrid particles. Immunization in complete or incomplete Freund's adjuvant or alum resulted in equivalent anti-HBc and anti-CS humoral responses. Examination of T cell recognition of HBcAg-CS particles revealed that HBcAg-specific T cells were universally primed and CS-specific T cells were primed if the insert contained a CS-specific T cell recognition site. This indicates that the internal site in HBcAg is permissive for the inclusion of heterologous pathogen-specific T as well as B cell epitopes. Most importantly, 90 and 100% of BALB/c mice immunized with HBcAg-CS1 particles were protected against a P. berghei challenge infection in two independent experiments. Therefore, hybrid HBcAg-CS particles may represent a useful approach for future malaria vaccine development.

Animals↗