Standards of professional practices for dietetics professionals in management and foodservice settings.
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Dietetics↗
Biomedical subjects
J M Dunn
Publications and source records attributed to J M Dunn.
CROC-4: a novel brain specific transcriptional activator of c-fos expressed from proliferation through to maturation of multiple neuronal cell types.
A novel, brain-specific cDNA, denoted CROC-4, was cloned from human brain by a contingent replication of cDNA procedure capable of detecting transcriptional activators of the human c-fos proto-oncogene promoter. CROC-4 encoded an 18-kDa serine/threonine-rich polypeptide containing a P-loop motif and an SH3-binding region with phosphorylation sites for a variety of protein kinases (cdc2, CDK2, MAPK, CDK5, protein kinase C, Ca(2+)/calmodulin protein kinase 2, casein kinase 2) involved in cell proliferation and differentiation. Immunohistochemistry revealed that during early development, expression was associated with proliferating and migrating cells throughout the rodent brain, initially appearing in the proliferative ventricular zones. During late development and in adult human brain, CROC-4 was expressed in diverse brain regions including the thalamus, subthalamic nucleus, corpus callosum, substantia nigra, caudate nucleus, amygdala, and hippocampus. The association of CROC-4 expression with proliferating regions of developing brain and retention in regions of the adult brain, as well as the punctate nuclear location, suggest that CROC-4 participates in brain-specific c-fos signaling pathways involved in cellular remodeling of brain architecture.
Adult↗
Selectable in-vivo recombination to increase antibody library size--an improved phage display vector system.
Phage display technology permits the display of libraries of random combinations of light (LC) and heavy chain (HC) antibody genes. Maximizing the size of these libraries would enable the isolation of antibodies with high affinity and specificity. In this study, the loxP/Cre system of in-vivo recombination has been employed to construct an improved vector system for the display of antibodies. In this system, the chloramphenicol acetyl transferase (CAT) gene is linked to a HC library in a donor plasmid, pUX. This CAT gene is 'silent' before recombination but active after recombination. A second acceptor phagemid, pMOX, is used for cloning the LC repertoire. Following infection with a Cre producing phage, pMOX accepts the CAT/HC library from pUX via site-specific recombination at the loxP sites. Recombinants can then be selected via chloramphenicol resistance. Using this vector system, we have generated libraries of 4x109 recombinants. Restriction analysis and Fab expression confirmed that 100% of the colonies in the library were recombinants. This system provides a stable selectable mechanism for the generation of large libraries and avoids the isolation of non-recombinants encountered with earlier in-vivo recombination systems.
Bacteriophages↗
High performance DNA sequencing, and the detection of mutations and polymorphisms, on the Clipper sequencer.
The Visible Genetics Clipper sequencer is a new platform for automated DNA sequencing which employs disposable MicroCel cassettes and 50 microm thick polyacrylamide gels. Two DNA ladders can be analyzed simultaneously in each of 16 lanes on a gel, after labeling with far-red absorbing dyes such as Cy5 and Cy5.5. This allows a simultaneous bidirectional sequencing of four templates. We have evaluated the Clipper sequencer, by cycle-sequencing of an M13 single-stranded DNA standard, and by coupled amplification and sequencing (CLIP) of reverse-transcribed human immunodeficiency virus (HIV-1) RNA standards and clinical patient samples. (i) Limitations of instrument. We have examined basic instrument parameters such as detector stability, background, digital sampling rate, and gain. With proper usage, the optical and electronic subsystems of the Clipper sequencer do not limit the data collection or sequence-determination processes. (ii) Limitations of gel performance. We have also examined the physics of DNA band separation on 50 microm thick MicroCel gels. We routinely obtain well-resolved sequence which can be base-called with 98.5% accuracy to position approximately 450 on an 11 cm gel, and to position approximately 900 on a 25 cm gel. Resolution on 5 and 11 cm gels ultimately is limited by a sharp decrease in spacing between adjacent bands, in the biased reptation separation regime. Fick's (thermal) diffusion appears to be of minor importance on 6 cm or 11 cm gels, but becomes an additional resolution-limiting factor on 25 cm gels. (iii) Limitations of enzymology. Template quality, primer nesting, choice of DNA polymerase, and choice between dye primers and dye terminators are key determinants of the ability to detect mutations and polymorphisms on the Clipper sequencer, as on other DNA sequencers. When CLIP is used with dye-labeled primers and a DNA polymerase of the F667Y, delta(5'--> 3' exo) class, we can routinely detect single-nucleotide mutations and polymorphisms over the 0.35-0.65 heterozygosity range. We present an example of detecting therapeutically relevant mutations in a clinical HIV-1 RNA isolate.
Bacteriophage M13↗
Pharmacokinetics of oral zidovudine entrapped in biodegradable nanospheres in rabbits.
The pharmacokinetic profile of oral zidovudine entrapped in a 50:50 polyactide-coglycolide matrix (nanospheres) was compared to those of standard oral and parenteral zidovudine formulations in rabbits. The bioavailability of zidovudine nanospheres at 50 mg/kg of body weight was 76%, and this dose achieved prolonged exposure to zidovudine compared to standard formulations without an increase in the drug's peak concentration.
Animals↗
Nutritional abnormalities in HIV/AIDS.
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Acquired Immunodeficiency Syndrome↗
High-speed DNA sequencing in ultrathin slab gels.
There have been many recent theoretical and technical advances in the sequencing of DNA in ultrathin slab gels. These include recent experimental progress in four areas: DNA polymerases; DNA template preparation; the separation and detection of DNA bands; and base-calling algorithms. The Zimm-Lumpkin theory of electrophoresis provides a new and improved framework for understanding the operation of sequencing gels.
Algorithms↗
Deletion of RB exons 24 and 25 causes low-penetrance retinoblastoma.
A deletion in the tumor-suppressor gene, RB, discovered by quantitative multiplex PCR, shows low penetrance (LP), since only 39% of eyes at risk in this family develop retinoblastoma. The 4-kb deletion spanning exons 24 and 25 (delta24-25) is the largest ever observed in an LP retinoblastoma family. Unlike the usual RB mutations, which cause retinoblastoma in 95% of at-risk eyes and yield no detectable protein, the delta24-25 allele transcribed a message splicing exon 23 to exon 26, resulting in a detectable protein (pRBdelta24-25) that lacks 58 amino acids from the C-terminal domain, proving that this domain is essential for suppression of retinoblastoma. Two functions were partially impaired by delta24-25-nuclear localization and repression of E2F-consistent with the idea that LP mutations generate "weak alleles" by reducing but not eliminating essential activities. However, delta24-25 ablated interaction of pRB with MDM2. Since a homozygous LP allele is considered nontumorigenic, the pRB/MDM2 interaction may be semi- or nonessential for suppressing retinoblastoma. Alternatively, some homozygous LP alleles may not cause tumorigenesis because an additional event is required (the "three-hit hypothesis"), or the resulting imbalance in pRB function may cause apoptosis (the "death allele hypothesis"). pRBdelta24-25 was also completely defective in suppressing growth of Saos-2 osteosarcoma cells. Targeting pRBdelta24-25 to the nucleus did not improve Saos-2 growth suppression, suggesting that C-terminal domain functions other than nuclear localization are essential for blocking proliferation in these cells. Since delta24-25 behaves like a null allele in these cells but like an LP allele in the retina, pRB may use different mechanisms to control growth in different cell types.
Canada↗
Plasma catecholamine and lactate relationship during graded exercise in men with spinal cord injury.
Catecholamine and lactate responses to incremental exercise were examined in individuals with spinal cord injury (SCI). Three men with high-level (HINJ) and four with low-level (LINJ) SCI performed VO2peak exercise tests on an arm ergometer. Forearm venous blood samples taken at rest and at the end of each work stage were analyzed for norepinephrine (NE), epinephrine (EPI), and lactate (LA) content. Mann-Whitney tests revealed that peak LA, NE, and EPI responses were greater in LINJ compared with HINJ subjects (LA = 7.1 +/- 0.5 vs 3.2 +/- 0.4 mM; NE = 3.1 +/- 1.0 vs 0.4 +/- 0.1 ng.ml-1; EPI = 0.5 +/- 0.2 vs 0.1 +/- 0.01 ng.ml-1). Spearman rank correlations for LINJ and HINJ groups were NE-EPI, rs = 0.85 vs rs = 0.17; NE-LA, rs = 0.83 vs rs = 0.31; and EPI-LA, rs = 0.73 vs rs = 0.41. The strong relationships between NE, EPI, and LA in the LINJ group were similar to those previously reported in able-bodied athletes. However, the relatively weak association between these factors in the HINJ group indicates that, while some function exits, the sympathoadrenal response to exercise is significantly impaired in these individuals. These results suggest that mechanisms other than catecholamines are primarily responsible for muscle lactate production during incremental exercise in individuals with HINJ.
Adrenal Cortex↗
X inactivation analysis and DNA methylation studies of the ubiquitin activating enzyme E1 and PCTAIRE-1 genes in human and mouse.
Previously reported data on the X inactivation status of the ubiquitin activating enzyme E1 (UBE1) gene have been contradictory, and the issue has remained unsettled. Here we present three lines of evidence that UBE1 is expressed from the inactive X chromosome and therefore escapes X inactivation. First, by RNA in situ hybridization, UBE1 RNA is detected from both the active and inactive X chromosomes in human female fibroblasts. Second, UBE1 is expressed in a large panel of somatic cell hybrids retaining inactive human X chromosomes, including two independent hybrids that did not require UBE1 expression for survival. And third, sites at the 5' end of UBE1 are unmethylated on both active and inactive X chromosomes, consistent with the gene escaping inactivation. In order to address whether other genes that escape inactivation map to the same region of the X chromosome, we have also examined the expression of genes mapping adjacent to UBE1. The gene for PCTAIRE-1 (PCTK1) maps within 5 kb of UBE1 and similarly escapes X inactivation by the somatic cell hybrid assay, whereas six other genes that are within 1 Mb of UBE1 in Xp11.23 are silenced on the inactive X chromosome. Comparative mapping studies of the homologous loci in mouse establish that Ube1-x and Pctk1 are also within close physical proximity on the murine X chromosome, and expression studies of the Pctk1 gene determine that, similar to Ube1-x, it is subject to X inactivation in mouse. Methylation of CpG residues at restriction sites at the 5' end of both genes on the murine inactive X chromosome is consistent with both genes being subject to X inactivation in mouse, in contrast to their expression status in humans.
Animals↗
Exfoliative cytology in the diagnosis of breast disease.
A total of 393 nipple discharge or scrape smears from 360 women were examined cytologically over a 12-year period. Twenty-nine breast cancers (8 per cent) have been histologically confirmed in this group, of which 16 had malignant smear cytology (sensitivity 55 per cent). Nine patients with breast cancer and positive cytology had impalpable tumours. Two of these cancers were not detected by any other investigation. Thirteen patients with nipple discharge had false-negative cytology, but there were no false-positive results (specificity 100 per cent). All patients with expressible or spontaneous nipple discharges and those with skin changes at the nipple should undergo examination of cytological smears.
Breast Neoplasms↗
The Grb2 binding domain of mSos1 is not required for downstream signal transduction.
Cellular Ras proteins are activated primarily by specific guanine-nucleotide releasing factors such as the Son of Sevenless (Sos) proteins. This activation event is thought to occur in response to plasma membrane localization of a complex containing Sos and a small adapter protein Grb2. We have isolated a dominant mutant allele of mSos1 which transforms Rat1 cells, yet is no longer able to bind Grb2. Biochemical experiments reveal that the subcellular distribution of this truncated Sos protein is not altered with respect to the wild type Sos protein. These data argue against a role for Grb2 in the direct recruitment of Sos proteins to the plasma membrane and suggest that Grb2 may function to overcome negative regulation of Sos by its C terminus.
Adaptor Proteins, Signal Transducing↗
Surgical treatment for venous ulcers: is it worthwhile?
We have reviewed the results of treatment of 159 consecutive limbs presenting with a clinical diagnosis of venous ulcer in 140 patients (70 male, aged 28-90 years, median 66 years). Of the patients, 61% were referred because of severe pain and 53% of the ulcers had been present > 2 years. Patients were evaluated clinically and by Doppler, with selective use of venography, photoplethysmography, arteriography and latterly duplex scanning. Seventy-one limbs had surgery to the superficial veins, 18 limbs had arterial reconstruction, and 10 limbs had skin grafting alone. There was one operative death after arterial reconstruction but none after venous surgery. Patients were followed up for 1-5 years (median 3 years). Of those who had been treated surgically, healing was achieved in 88%, and ulcers healed in 52% of those treated non-operatively. In all, 18% of the ulcers recurred in each group. These results show a favourable association between appropriate venous and arterial surgery and the healing of venous ulcers, with relief of pain. They support a policy of thorough evaluation and appropriate surgical treatment in these patients.
Adult↗
Comparison of radioligand assay and immunostaining for epidermal growth factor receptor in human breast cancer.
Epidermal growth factor (EGF) receptor status is a useful prognostic indicator in women with breast cancer. Lack of standardization and correlation of methodology for the detection of EGF receptor has hampered its further evaluation. EGF receptor status was ascertained by immunohistochemistry and radioligand assay in 120 breast cancers. Of 52 tumours negative for EGF receptor on radioligand assay, 47 were negative on immunohistochemistry and, of 68 tumours positive for the receptor on assay, 52 were positive on immunohistochemistry. If the more widely evaluated radioligand assay is assumed to be the 'gold standard', immunohistochemistry has a sensitivity of 81 per cent and a specificity of 91 per cent.
Biomarkers, Tumor↗
Chronic alterations in cardiac mechanics after fetal closed heart operation.
Pulmonary artery banding was performed in 8 fetal sheep at 125 days' gestation to evaluate the feasibility of fetal closed cardiac operation. At 135 days' gestation, the fetuses were delivered and the cardiac mechanics were evaluated using a modified Langendorff isolated heart preparation. Two of the 8 fetuses aborted spontaneously 2 and 7 days after operation. Six fetuses (75%) survived the 10 days after delivery. The left ventricular cardiac mechanics in the banded fetuses (group I) were compared with those in 8 control fetuses (group II). All fetal hearts in both groups displayed a significant volume-pressure relationship. The volume-pressure curve was found to be shifted upward and to the left in the fetal hearts after pulmonary artery banding. The left ventricles subjected to increased in utero preload secondary to pulmonary artery banding were capable of generating greater peak systolic and developed pressures. Because the fetal heart manifests a Starling type of preload reserve, as such, it demonstrates that the possibility exists for subsequent fetal development to be altered by intrauterine intervention.
Animals↗
Scrape cytology in the diagnosis of Paget's disease of the breast.
Eczema of the nipple is an important symptom presenting to the general surgeon in the out-patient department. The diagnosis of Paget's disease of the nipple has traditionally been made by incision biopsy necessitating at least a local anaesthetic. We present 14 patients with nipple skin change, in whom the technique of scrape cytology was used to identify patients with Paget's disease. In our series eight cases of Paget's disease were successfully identified by scrape cytology with no false negatives or positives. We suggest that this is a quick, easy, non-invasive method of screening eczema of the nipple in the out-patient clinic.
Breast Diseases↗
Outpatient clinic review after arterial reconstruction: is it necessary?
After arterial reconstruction, patients have traditionally been followed up in clinic in the long term. We have pursued a policy of limited clinic follow-up, with an 'open access' service for suspected graft failure (and latterly duplex scanning surveillance for vein grafts). This policy was assessed by measurement of the success of self-referral, graft patency and patient satisfaction after operation for lower limb ischaemia in 173 patients. At median follow-up of 50 months, 61 (35%) patients had died and 45 (25%) had required amputation. Of those with salvaged limbs and available for follow-up, 55 (86%) patients reported continuing symptomatic improvement with a graft patency rate of 80%. During the review period, 27 (42%) patients had presented themselves on suspicion of graft occlusion and 14 (52%) of these had required surgical intervention. Of the patients, 45 (70%) found a single postoperative clinic visit helpful, and the majority thought that further visits would not have been helpful to them. Limited clinic appointments seem especially desirable for elderly patients for whom journeys are an imposition, as well as reducing travel costs, and giving surgeons more time to deal with new referrals. These results suggest that properly educated patients present themselves when signs of graft occlusion occur, and there is little to be gained by regular long-term clinic follow-up in vascular surgical practice.
Adult↗
Medullary thyroid carcinoma.
Medullary thyroid carcinoma accounts for 5-10 per cent of thyroid malignancies and occurs sporadically, and in three familial settings with autosomal dominant inheritance. Calcitonin, a 32 amino acid 3.5-kDa protein, is a biochemical marker of the tumour. Serum levels correlate with disease burden. Treatment initiated by screening allows disease removal at a premalignant phase: C cell hyperplasia. Genetic linkage studies locate the multiple endocrine neoplasia type 2A gene near the centromere of chromosome 10. Flanking genetic markers may allow polymorphic probes to examine DNA from a once-only blood sample to identify affected individuals. At what age thyroidectomy should be carried out in these patients is unclear.
Biomarkers, Tumor↗