Epithelial downgrowth following clear cornea phacoemulsification in a buphthalmic eye.
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Adult↗
Biomedical subjects
D H Jones
Publications and source records attributed to D H Jones.
Linear sebaceous naevus syndrome and resistant rickets.
The association between vitamin-D-resistant rickets and linear sebaceous naevus syndrome is extremely rare. Only eight cases have been described in the English literature and in none were the skeletal aspects addressed. We present three new cases and describe the musculoskeletal features. The details and outcome of surgery for correction of the deformities are discussed. The disturbances of metabolism of vitamin D and the effects of pharmacological treatment are also described.
Calcitriol↗
The mouse Na+-K+-ATPase gamma-subunit gene (Fxyd2) encodes three developmentally regulated transcripts.
The Na(+)-K(+)-ATPase is understood to function as a hetero-oligomer of alpha- and beta-subunits, but a third subunit, gamma, has been proposed to influence the enzyme's catalytic function. Recently, two variants of the gamma-subunit have been described in kidney, raising the possibility of multiple gamma-subunits with diverse functions. We now report the cloning and sequencing of the mouse gamma-subunit gene (Fxyd2). Analysis of the structure of the gene shows that it encodes three mRNAs that have distinct NH(2)-terminal (extracellular) encoding sequences but common transmembrane and COOH-terminal-encoding sequences resulting from differential splicing and, probably, alternate promoter usage. The three mRNAs have tissue-specific expression patterns. The existence of three different extracellular domains of the gamma-variants and how they may interact with the sodium pump to alter its cation transport properties must now be taken into account for future understanding of the modulation of the Na(+)-K(+)-ATPase by its gamma-subunit.
Alternative Splicing↗
A novel microencapsulated peptide vaccine against hepatitis B.
A 48 amino acid synthetic peptide (S121/48) representing residues 121-167 of the major envelope protein of hepatitis B virus (HBsAg) was successfully encapsulated into polylactide co-glycolide microspheres. A single immunization of the microspheres in BALB/c (H-2d) mice resulted in the production of high-titre anti-HBs antibodies (IgG1-type). The response was long lasting and was superior to that obtained using the same peptide adjuvanted with Freund's complete adjuvant. A T-cell memory response was detected 10 weeks after a booster immunization (approximately 35 weeks after initial immunization) as measured by in-vitro re-stimulation of splenocytes. This study illustrates the feasibility of a single dose vaccine for hepatitis B and is, to our knowledge, the first demonstration of a synthetic peptide immunogen inducing anti-native protein antibodies of comparable titre to those obtained with conventional vaccines for hepatitis B. The suitability of a synthetic peptide vaccine for hepatitis B is discussed.
Amino Acid Sequence↗
Recombinant pre-pro-Concanavalin A (jack bean) is stable but of low solubility.
The cDNA for pre-pro-Concanavalin A (pre-pro-ConA) was cloned into the cytoplasmic expression vector pKK233-2 to give rise to pCONEXP2 which was used to express the lectin precursor. Pre-pro-ConA is stable and is not transposed and ligated to form the mature protein. No signal peptide removal is observed. The solubility of pre-pro-ConA could not be increased by guanidine hydrochloride denaturation/dilution treatment.
Blotting, Western↗
A new surgical technique for keratoglobus-tectonic lamellar keratoplasty followed by secondary penetrating keratoplasty.
PURPOSE: To develop a technique that achieves satisfactory visual rehabilitation in keratoglobus, without the problems of re-epithelialization failure and with minimal risk of graft rejection. METHODS: A patient with bilateral keratoglobus and visual acuities of light perception in the right eye and 6/60 in the left underwent a tectonic lamellar keratoplasty to the right eye. The cornea was first trephined to the depth of the anterior stroma within the limbus. A lamellar dissection technique then was used to tunnel into sclera under the limbus to preserve stem cells. The host corneal epithelium was completely débrided, and a donor corneoscleral button, denuded of its endothelium, was laid on top. A paracentesis was made, and aqueous was aspirated until the anterior chamber had collapsed enough to take up a more physiologic shape. The donor corneoscleral graft was sutured into the prefashioned scleral bed with long, interrupted sutures. Once in situ, the donor graft was débrided of epithelium, and the host limbus was sutured on to it, covering its scleral component. Six months later, a penetrating keratoplasty was performed. The same procedure was performed on the left eye 2 years later. RESULTS: The right eye maintained a best-corrected visual acuity of 6/60 for 16 months after the penetrating graft until the graft decompensated, leaving a final acuity of counting fingers. The left eye maintained a best-corrected visual acuity of 6/18. CONCLUSION: Tectonic lamellar keratoplasty to preserve the host limbus, followed by secondary penetrating keratoplasty, is a realistic alternative to other procedures for the surgical management of keratoglobus.
Cornea↗
Menjugate (Chiron).
Chiron has developed and launched Menjugate, a vaccine for the treatment for meningococcus C infections caused by the pathogen Neisseria meningitidis [177064]. In August 1999, Chiron filed with the UK MCA for a license to market Menjugate. The licence was granted in March 2000 [339082], [344773], [357897] and as of April 2000, a vaccination program was underway in the UK [362152]. Menjugate is indicated for children of 12 months and older, but Chiron was expecting approval in the US for infants younger than 12 months by the end of 2000. The company will also pursue mutual recognition in Europe [376204]. In August 2000, Chiron received marketing clearance for Menjugate from the Irish Medicines Board as a conjugate against meningococcal C disease [378353]. The vaccine employs CRM-conjugate technology, whereby a diphtheria toxoid is used as a carrier protein for the meningitis C-specific antigens. The vaccine is being developed for its potential to provide protection against meningitis in both adults and infants. In July 2000, Chiron entered into a comarketing and co-promotion agreement with Aventis Pasteur under which Aventis will assist Chiron in marketing and sales efforts for Menjugate in the UK [374760].
Clinical Trials as Topic↗
Tetracel (American Home Products).
American Home Products (AHP) is developing Tetracel as a vaccine for children (aged 12 to 18 months) against diphtheria, tetanus, pertussis and Haemophilus influenzae type B (Hib) [275146]. The components are contained in AHP's two currently marketed vaccines. ACEL-Immune contains diphtheria and tetanus toxoids with acellular pertussis vaccine adsorbed, and HibTITER contains the Haemophilus influenzae B conjugate vaccine (diphtheria CRM197 protein conjugate) [239655]. As of January 2000, Lehman Brothers predicted Tetracel to be approved in the US during 2000 [354434].
Clinical Trials as Topic↗
Panhandle PCR for cDNA: a rapid method for isolation of MLL fusion transcripts involving unknown partner genes.
Identifying translocations of the MLL gene at chromosome band 11q23 is important for the characterization and treatment of leukemia. However, cytogenetic analysis does not always find the translocations and the many partner genes of MLL make molecular detection difficult. We developed cDNA panhandle PCR to identify der(11) transcripts regardless of the partner gene. By reverse transcribing first-strand cDNAs with oligonucleotides containing coding sequence from the 5' MLL breakpoint cluster region at the 5' ends and random hexamers at the 3' ends, known MLL sequence was attached to the unknown partner sequence. This enabled the formation of stem-loop templates with the fusion point of the chimeric transcript in the loop and the use of MLL primers in two-sided PCR. The assay was validated by detection of the known fusion transcript and the transcript from the normal MLL allele in the cell line MV4-11. cDNA panhandle PCR then was used to identify the fusion transcripts in two cases of treatment-related acute myeloid leukemia where the karyotypes were normal and the partner genes unknown. cDNA panhandle PCR revealed a fusion of MLL with AF-10 in one case and a fusion of MLL with ELL in the other. Alternatively spliced transcripts and exon scrambling were detectable by the method. Leukemias with normal karyotypes may contain cryptic translocations of MLL with a variety of partner genes. cDNA panhandle PCR is useful for identifying MLL translocations and determining unknown partner sequences in the fusion transcripts.
Alleles↗
Differential involvement of Na(+),K(+)-ATPase isozymes in preimplantation development of the mouse.
Na(+),K(+)-ATPase plays an essential role in mammalian blastocoel formation (cavitation) by driving trans-epithelial sodium transport. Previously, the alpha1 and beta1 subunit isoforms of this enzyme were identified in preimplantation mouse embryos and were assumed to be responsible for this function. Here we show that mRNAs encoding an additional alpha subunit isoform (alpha3) and the remaining two beta subunit isoforms are also present in preimplantation embryos. Whereas alpha3 mRNA accumulates between the four-cell and the blastocyst stages and thus results from embryonic transcription, the same could not be demonstrated for beta2 and beta3 mRNAs. Immunoblot analyses confirmed that these subunits are present in cavitating embryos. Using confocal immunofluorescence microscopy we found that alpha1 and beta1 subunits are concentrated in the basolateral membranes of the trophectoderm while being equally distributed in plasma membranes of the inner cell mass. In contrast, alpha3, beta2, and beta3 subunits were not detected in plasma membranes. Our current assessment, therefore, is that as many as six isozymes of Na(+),K(+)-ATPase could be involved in preimplantation development although it is primarily the alpha1beta1 isozyme that is responsible for blastocoel formation. Our findings imply that the regulation of sodium transport within the preimplantation mouse embryo is more complex than had been appreciated.
Animals↗
Type I phosphatidylinositol 4-phosphate 5-kinase directly interacts with ADP-ribosylation factor 1 and is responsible for phosphatidylinositol 4,5-bisphosphate synthesis in the golgi compartment.
Phosphatidylinositol (PtdIns) 4,5-bisphosphate is involved in many aspects of membrane traffic, but the regulation of its synthesis is only partially understood. Golgi membranes contain PI 4-kinase activity and a pool of phosphatidylinositol phosphate (PIP), which is further increased by ADP-ribosylation factor 1 (ARF1). COS7 cells were transfected with alpha and beta forms of PI 4-kinase, and only membranes from COS7 cells transfected with PI 4-kinase beta increased their content of PIP when incubated with ARF1. PtdIns(4, 5)P(2) content in Golgi membranes was nonexistent but could be increased to a small extent upon adding either cytosol or Type I or Type II PIP kinases. However, when ARF1 was present, PtdIns(4,5)P(2) levels increased dramatically when membranes were incubated in the presence of cytosol or Type I, but not Type II, PIP kinase. To examine whether ARF1 could directly activate Type I PIP 5-kinase, we used an in vitro assay consisting of phosphatidycholine-containing liposomes, ARF1, and PIP 5-kinase. ARF1 increased Type I PIP 5-kinase activity in a guanine nucleotide-dependent manner, identifying this enzyme as a direct effector for ARF1.
ADP-Ribosylation Factor 1↗
Detection of leukemia-associated MLL-GAS7 translocation early during chemotherapy with DNA topoisomerase II inhibitors.
Leukemias with MLL gene translocations are a complication of primary cancer treatment with DNA topoisomerase II inhibitors. How early translocations appear during primary cancer treatment has not been investigated. We tracked the leukemic clone with an MLL gene translocation during neuroblastoma therapy in a child who developed acute myeloid leukemia. The karyotype of the leukemic clone showed del(11)(q23). We used panhandle PCR-based methods to isolate the breakpoint junction involving MLL and an unknown partner gene. Marrow DNA from neuroblastoma diagnosis and DNA and RNA from serial preleukemic marrows were examined for the translocation. The karyotypic del(11)(q23) was a cryptic t(11;17). GAS7, a growth arrest-specific gene at chromosome band 17p13, was the partner gene of MLL. Two different MLL-GAS7 fusion transcripts were expressed. The translocation was already detectable by 1.5 months after the start of neuroblastoma treatment. The translocation was not detectable in the marrow at neuroblastoma diagnosis or in peripheral blood lymphocyte DNAs of six normal subjects. GAS7 is a new partner gene of MLL in treatment-related acute myeloid leukemia. MLL gene translocations can be present early during anticancer treatment at low cumulative doses of DNA topoisomerase II inhibitors. Although MLL has many partner genes and most have not been characterized, panhandle PCR strategies afford new means for detecting MLL gene translocations early during therapy when the partner gene is unknown.
Adolescent↗
Expression and membrane assembly of a transmembrane region from Neu.
Transmembrane domains of receptor tyrosine kinases are increasingly seen as key modulatory elements in signaling pathways. The present work addresses problems surrounding expression, isolation, secondary structure recovery, and assembly into membranes, of the relatively large quantities of transmembrane peptides needed to investigate these pathways by NMR spectroscopy. We demonstrate significant correspondence between SDS-PAGE behavior of such peptides and their (2)H NMR spectra in lipid bilayer membranes. A 50-residue peptide, Neu(exp), containing the transmembrane portion of the receptor tyrosine kinase, Neu, was designed for expression in Escherichia coli. The sequence also contained 11-12 amino acids from each side of the transmembrane domain. The common problem of low expressivity of transmembrane peptides was encountered-likely associated with membrane toxicity of the desired gene product. This difficulty was overcome by expressing the peptide as a TrpE fusion protein in a pATH vector to target expression products to inclusion bodies, and subsequently removing the TrpE portion by cyanogen bromide cleavage. Inclusion bodies offered the additional benefits of reduced proteolytic degradation and simplified purification. The presence of a hexa-His tag allowed excellent recovery of the final peptide, while permitting use of denaturing solvents and avoiding the need for HPLC with its attendant adsorption losses. Isolated expressed peptides were found to be pure, but existed as high oligomers rich in beta-structure as evidenced by CD spectroscopy and SDS-PAGE behavior. Dissolution in certain acidic organic solvents led to material with increased alpha-helix content, which behaved in detergent as mixtures of predominantly monomers and dimers-a situation often considered to exist in cell membranes. For purposes of NMR spectroscopy, peptide alanine residues were deuterated in high yield during expression. The same acidic organic solvents used to dissolve and dissociate expressed transmembrane peptides proved invaluable for their assembly into lipid bilayers. Analogous transmembrane peptides from the human receptor tyrosine kinase, ErbB-2, demonstrated related phenomena.
Amino Acid Sequence↗
Subthalamic nucleus microinjections of 5-HT2 receptor antagonists suppress stereotypy in rats.
The subthalamic nucleus (STN) is an important mediator of basal ganglia output. We studied the effects of STN microinjections of the serotonin-2 (5-HT2) antagonists clozapine, mesulergine and M100,907 on apomorphine-induced stereotypic activity in the rat. Each compound profoundly decreased the expression of stereotypic behavior, with particularly strong effects to reduce gnawing behavior. Because M100,907 does not have appreciable affinity for dopamine D1 and D2 receptors, and since all three agents are 5-HT2 antagonists, the current data suggest that basal ganglia output related to orofacial movements can be significantly modified by 5-HT2 receptors. The results suggest that antipsychotics with serotonergic properties may have direct actions on the STN that influence their potential to produce orofacial and other motor side effects.
Animals↗
A massive pulmonary tumor embolism after surgical manipulation and biopsy of a pelvic mass.
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Anesthesia, Inhalation↗
The new hospice compliance plan: defining and addressing risk areas.
The Department of Health and Human Services' (HHS) Office of the Inspector General (OIG), has advised hospices and other health care providers to formulate effective controls to ensure compliance with federal and state statutes, rules, and regulations, and private-payor health care program requirements. The recently released guidelines provide a blueprint for developing such programs. This is the first of four installments that focus specifically on the 28 risk areas identified in the guidance and offer strategies for incorporating them in a hospice compliance program. The authors have organized the 28 risk areas under 9 topic domains to simplify the task of tackling the guidance. This article covers the first two areas: Admission/Certification/Recertification and Billing.
Certification↗
The new hospice compliance plan: defining and addressing risk areas. Part 2.
The Department of Health and Human Services' (HHS) Office of the Inspector General (OIG), has advised hospices and other health care providers to formulate effective controls to ensure compliance with federal and state statutes, rules, and regulations, and private-payor health care program requirements. This is the second of three installments that focus specifically on the 28 risk areas identified in the guidance and offer strategies for incorporating them in a hospice compliance program. This article covers the areas of Expensive Care, Documentation, Interdisciplinary Group, and Kickbacks.
Documentation↗
The new hospice compliance plan: defining and addressing risk areas. Part 3.
The recently released OIG guidelines to ensure compliance with federal and state statutes, rules, and regulations, and private-payor health care program requirements provide a blueprint for developing such programs. This is the last of three installments that focus specifically on the 28 risk areas identified in the guidance and offer strategies for incorporating them in a hospice compliance program. The authors have organized the 28 risk areas under 9 topic domains to simplify the task of tackling the guidance. This article covers the areas of nursing home care, marketing, and Conditions of Participation.
Guideline Adherence↗