Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member.
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Base Sequence↗
Biomedical subjects
D Church
Publications and source records attributed to D Church.
Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member.
Using positional cloning strategies, we have identified a CTG triplet repeat that undergoes expansion in myotonic dystrophy patients. This sequence is highly variable in the normal population. PCR analysis of the interval containing this repeat indicates that unaffected individuals have been 5 and 27 copies. Myotonic dystrophy patients who are minimally affected have at least 50 repeats, while more severely affected patients have expansion of the repeat containing segment up to several kilobase pairs. The CTG repeat is transcribed and is located in the 3' untranslated region of an mRNA that is expressed in tissues affected by myotonic dystrophy. This mRNA encodes a polypeptide that is a member of the protein kinase family.
Amino Acid Sequence↗
Cloning of the alpha-adducin gene from the Huntington's disease candidate region of chromosome 4 by exon amplification.
We have applied the technique of exon amplification to the isolation of genes from the chromosome 4p16.3 Huntington's disease (HD) candidate region. Exons recovered from cosmid Y24 identified cDNA clones corresponding to the alpha-subunit of adducin, a calmodulin-binding protein that is thought to promote assembly of spectrin-actin complexes in the formation of the membrane cytoskeleton, alpha-adducin is widely expressed and, at least in brain, is encoded by alternatively spliced mRNAs. The alpha-adducin gene maps immediately telomeric to D4S95, in a region likely to contain the HD defect, and must be scrutinized to establish whether it is the site of the HD mutation.
Alternative Splicing↗
A novel G protein-coupled receptor kinase gene cloned from 4p16.3.
Within the Huntington's disease (HD) candidate region of 4p16.3, the D4S127 locus displays strong linkage disequilibrium with the defect and anchors a conserved haplotype found on many HD chromosomes. To isolate genes from this region we have applied the exon amplification technique to overlapping cosmids spanning D4S127. Here, we report the discovery of a new gene encoding a novel member of a family of protein kinases that specifically phosphorylate the activated forms of G protein-coupled receptors. Such kinases are thought to participate in desensitization of specific receptors, thereby blocking further signal transduction. This gene must now be carefully scrutinized to determine whether it might be involved in HD.
Amino Acid Sequence↗
Postoperative respiratory function after laparoscopic cholecystectomy.
Open cholecystectomy causes changes in pulmonary function test volumes; such changes can be related to respiratory complications of hypoxemia and atelectasis. Little data is available on lung volume changes after laparoscopic cholecystectomy. We measured preoperative and postoperative vital capacity (VC), functional residual capacity (FRC), arterial PO2, and chest X-ray atelectasis in 31 patients undergoing laparoscopic cholecystectomy and found small but significant decreases (p < 0.01) in VC (13 +/- 19%) and FRC (7 +/- 17%). The PO2 decreased from 89 +/- 11 mm Hg to 82 +/- 14 mm Hg, with only one patient's PO2 less than 60 mm Hg. Three patients demonstrated new segmental lobar collapse on postoperative chest X-ray. The postoperative changes in FRC (R2 = 0.40, p < 0.04) and atelectasis (R2 = 0.46, p < 0.03) could be predicted by multiple regression of risk factors, including obesity, smoking, use of narcotics, age, and symptoms of prior respiratory disease. We conclude that the respiratory changes after laparoscopic surgery are small in comparison to those expected after open cholecystectomy.
Cholecystectomy, Laparoscopic↗
Protein synthesis requirements for nuclear division, cytokinesis, and cell separation in Saccharomyces cerevisiae.
Protein synthesis inhibitors have often been used to identify regulatory steps in cell division. We used cell division cycle mutants of the yeast Saccharomyces cerevisiae and two chemical inhibitors of translation to investigate the requirements for protein synthesis for completing landmark events after the G1 phase of the cell cycle. We show, using cdc2, cdc6, cdc7, cdc8, cdc17 (38 degrees C), and cdc21 (also named tmp1) mutants, that cells arrested in S phase complete DNA synthesis but cannot complete nuclear division if protein synthesis is inhibited. In contrast, we show, using cdc16, cdc17 (36 degrees C), cdc20, cdc23, and nocodazole treatment, that cells that arrest in the G2 stage complete nuclear division in the absence of protein synthesis. Protein synthesis is required late in the cell cycle to complete cytokinesis and cell separation. These studies show that there are requirements for protein synthesis in the cell cycle, after G1, that are restricted to two discrete intervals.
Cell Cycle↗
Iodine supplementation: comparison of oral or intramuscular iodized oil with oral potassium iodide. A controlled trial in Zaire.
A community-based controlled trial of iodine supplementation comparing oral or intramuscular iodized oil with oral potassium iodide has been carried out in 23 severely iodine-deficient villages in Eastern Zaire. The overall goitre prevalence in the population (n = 5999) was 61% and mean urinary iodine excretion in sample of 57 women 10.9 (SD 6.8) micrograms/g creatinine. All adults in three groups of four villages were given single doses of potassium iodide of 0.5 g, 1.0 g, and 2.0 g respectively. A fourth group was given oral iodized oil (2 ml) and a fifth placebo-treated. A further three villages were given intramuscular iodized oil (2 ml). The effectiveness of supplementation was assessed by measurements of bloodspot thyroxine (T4) concentration in women of reproductive age in the villages. The effects of iodide were small and inconsistent. Eight months after supplementation with oral iodized oil the distribution of T4 concentrations was similar to that seen with intramuscular oil. We conclude that oral iodized oil is an effective alternative to injected oil and would be feasible for iodine supplementation in remote areas with untrained people.
Administration, Oral↗
Saccharomyces cerevisiae fungemia: case report and review of the literature.
Saccharomyces cerevisiae was isolated on two separate occasions from the blood of a patient with chronic renal failure receiving dialysis. Treatment was complicated by recurrent ventricular tachycardia occurring after both 1 mg and 0.1 mg test doses of amphotericin. We report the unique clinical and microbiological aspects of this patient's management, and review the literature pertinent to this organism.
Humans↗
Acceptance of allogeneic fibroblasts in skin equivalent transplants.
Living skin equivalents (SE) were prepared by combining cultured fibroblasts with a collagen matrix and overlaying this lattice with keratinocytes. SEs prepared using allogeneic female rat fibroblasts or xenogeneic rabbit or human fibroblasts and keratinocytes isogeneic to the graft recipient were transplanted to recipient male rats. Biopsies of some of these SE grafts were examined histologically at intervals ranging from 5 days to 2 months. Biopsies of other grafts were done, and fibroblasts grown from them were karyotyped to determine the percentage of donor fibroblasts remaining in the graft. SEs containing xenogeneic fibroblasts were rejected. Allografted fibroblasts in SEs were accepted by recipient rats after a transient mononuclear cell response. A second SE allograft from the same donor strain did not provoke rejection either in the original allograft or in the challenge allograft. A secondary graft of allogeneic skin did not provoke rejection in the original SE graft, although the skin graft was rejected. Grafting the recipient first with allogeneic skin and then with the SE allograft led to rejection of the skin but not of the SE graft, ruling out the possibility that suppressor T cells were responsible for SE allograft acceptance. Allografted fibroblasts in SEs do not provoke a rejection response, even in presensitized animals, do not render the recipient tolerant to allogeneic skin, and do not act as targets when active rejection is taking place. We propose that cells bearing class I antigens may be acceptable graft constitutents if incorporated in a tissue equivalent excluding cells with class II antigens.
Animals↗
Structural integration of skin equivalents grafted to Lewis and Sprague-Dawley rats.
Bilayered skin equivalents, composed of a sheet of epidermal cells overlying a collagen lattice populated with fibroblasts, quickly become structurally integrated with the surrounding host skin after grafting to Lewis rats. Three days after transplantation, the skin equivalent lies on a bed of host granulation tissue and is loosely attached to the adjoining host dermis. Blood vessels begin to invade the collagen lattice by 5 days after grafting. By the 7th day a fully keratinized, hypertrophic epidermis covers the surface of the graft and blood vessels penetrate the lattice to the base of the epidermis. Vascularization of the graft is accompanied by activation and proliferation of the fibroblasts and by a condensation of the collagen matrix. During the 2nd week after grafting, the collagen fibrils become organized into thin fibers that show a basketweave pattern of birefringence when examined using polarized light. By 1 month the structure of the skin equivalent has become stabilized. The fibroblasts now resemble the quiescent fibrocytes of normal, resting dermis and the epidermis remains moderately hypertrophic. One to two years after grafting to Sprague-Dawley rats, the skin equivalents do not appear hypertrophic. The graft lacks secondary derivatives such as hair follicles and sweat glands, presumably because the stem cells are lost during the isolation of the epidermal cells. Grafts that are prepared using epidermal cells overlying a collagen gel without fibroblasts give rise to raised, linear scars within 2 weeks.
Animals↗
Fibroblasts in isogeneic skin equivalents persist for long periods after grafting.
We have fabricated skin equivalents by combining fibroblasts from female Fischer rats with collagen to form a lattice and overlaying the lattice with a suspension of epidermal cells. The epidermal cells attach and form a sheet which differentiates. These skin equivalents were then grafted to male Fischer rats in order to follow the fate of the fibroblasts after implantation. Biopsies of the skin equivalent were taken between 9 days and 13 months after grafting and examined histologically or placed in tissue culture to permit karyotyping of the resident fibroblasts. Approximately 82% of the fibroblasts from the graft biopsied at 9 days were female, with this proportion decreasing sharply to 50% at 2 weeks and 60-64% at 1 month. At 1 month, this initial sharp drop is followed by a slow, linear decline which continues through the 13th month when 42% of the fibroblasts are female. We conclude that fibroblasts of the grafted skin equivalent become permanent residents of the skin of the host rat.
Animals↗
The hospital care of East African children. Planning a paediatric unit. The architect's view.
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Africa, Eastern↗
Hypothalamic-pituitary sarcoidosis.
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Adrenal Cortex Hormones↗