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M Levine

Publications and source records attributed to M Levine.

At least 37 records · Page 2Linked to original sources
PubMed2001

A new recommended dietary allowance of vitamin C for healthy young women.

The recently released Recommended Dietary Allowance of vitamin C for women, 75 mg daily, was based on data for men. We now report results of a depletion-repletion study with healthy young women hospitalized for 186 +/- 28 days, using vitamin C doses of 30-2,500 mg daily. The relationship between dose and steady-state plasma concentration was sigmoidal. Only doses above 100 mg were beyond the linear portion of the curve. Plasma and circulating cells saturated at 400 mg daily, with urinary elimination of higher doses. Biomarkers of endogenous oxidant stress, plasma and urine F(2)-isoprostanes, and urine levels of a major metabolite of F(2)-isoprostanes were unchanged by vitamin C at all doses, suggesting this vitamin does not alter endogenous lipid peroxidation in healthy young women. By using Food and Nutrition Board guidelines, the data indicate that the Recommended Dietary Allowance for young women should be increased to 90 mg daily.

Adult↗
PubMed2001

Enzyme therapy for lysosomal acid lipase deficiency in the mouse.

Lysosomal acid lipase (LAL) is the critical enzyme for the hydrolysis of the triglycerides (TG) and cholesteryl esters (CE) delivered to lysosomes. Its deficiency produces two human phenotypes, Wolman disease (WD) and cholesteryl ester storage disease (CESD). A targeted disruption of the LAL locus produced a null (lal( -/-)) mouse model that mimics human WD/CESD. The potential for enzyme therapy was tested using mannose terminated human LAL expressed in Pichia pastoris (phLAL), purified, and administered by tail vein injections to lal( -/-) mice. Mannose receptor (MR)-dependent uptake and lysosomal targeting of phLAL were evidenced ex vivo using competitive assays with MR-positive J774E cells, a murine monocyte/macrophage line, immunofluorescence and western blots. Following (bolus) IV injection, phLAL was detected in Kupffer cells, lung macrophages and intestinal macrophages in lal( -/-) mice. Two-month-old lal( -/-) mice received phLAL (1.5 U/dose) or saline injections once every 3 days for 30 days (10 doses). The treated lal( -/-) mice showed nearly complete resolution of hepatic yellow coloration; hepatic weight decreased by approximately 36% compared to PBS-treated lal( -/-) mice. Histologic analyses of numerous tissues from phLAL-treated mice showed reductions in macrophage lipid storage. TG and cholesterol levels decreased by approximately 50% in liver, 69% in spleen and 50% in small intestine. These studies provide feasibility for LAL enzyme therapy in human WD and CESD.

Animals↗
PubMed2001

Clinical practice guidelines for the care and treatment of breast cancer: 13. Sentinel lymph node biopsy.

OBJECTIVE: To provide information and recommendations to women with breast cancer and their physicians regarding what is now known about sentinel lymph node (SLN) biopsy. OPTIONS: Axillary dissection; SLN biopsy followed by backup axillary dissection; SLN biopsy. OUTCOMES: Accurate determination of cancer stage, resulting in better-informed therapeutic decisions. EVIDENCE: Systematic review of English-language literature published from January 1991 to December 2000 retrieved primarily from MEDLINE and CANCERLIT. RECOMMENDATIONS: Axillary dissection is the standard of care for the surgical staging of operable breast cancer. If a patient requests or is offered SLN biopsy, the benefits and risks as well as what is and is not known about the procedure should be outlined. Patients should be informed of the number of SLN biopsies performed by the surgeon and the surgeon's success rate with the procedure, as determined by the identification of the SLN and the false-negative rate (the presence of tumour cells in the axillary nodes when the SLN biopsy result is negative). Before surgeons replace axillary dissection by SLN biopsy as the staging procedure at their institution, they should (a) familiarize themselves with the literature on the topic and the techniques needed to perform the procedure, (b) follow a defined protocol for all 3 aspects of the procedure (nuclear medicine, surgery, pathology) and (c) perform backup axillary dissection until an acceptable success rate (as determined by the identification of the SLN and the false-negative rate) is achieved. A surgeon who performs breast cancer surgery infrequently should not perform SLN biopsy. A positive SLN biopsy result or failure to identify an SLN should prompt full axillary dissection. SLN biopsy is contraindicated in women who have clinically palpable nodes, locally advanced breast cancer, multifocal tumours, previous breast surgery or previous irradiation of the breast. Staining of tissue sections with hematoxylin and eosin, and not immunohistochemical analysis for cytokeratin, should determine adjuvant therapy. Participation in randomized clinical trials is encouraged. [A patient version of these guidelines appears in Appendix 1.] VALIDATION: Internal validation within the Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer; no external validation.

Axilla↗
PubMed2001

A prospective trial of inhaled nitric oxide in clinical lung transplantation.

BACKGROUND: Reperfusion injury (RI) is a major cause of mortality and morbidity among lung transplant recipients. We sought to determine if prophylactic administration of inhaled nitric oxide (NO) to lung transplant recipients at reperfusion would prevent RI. We also hypothesized that if prophylactic NO proves ineffective in preventing RI then it may improve pulmonary hemodynamics and gas exchange in the subset of patients who develop RI. METHODS: After informed consent, 28 consecutive, adult lung transplant recipients received NO at 20 ppm at reperfusion. NO was withdrawn for 15 min at 6 and 12 hr after reperfusion, and gas exchange and hemodynamics were measured. RESULTS: Five of the 28 lung transplant recipients (18%) developed RI. Withdrawal of NO for 15 min in this subset of patients resulted in a significant rise in mean pulmonary artery pressure and a reduction in oxygenation index. All five patients with RI were kept on inhaled NO until full functional recovery of the allograft and were then weaned from mechanical ventilation. None required extracorporeal membrane oxygenation support; the early mortality in this group was 20% (1/5). The remaining 23 patients without RI had uneventful early postoperative course and were weaned from NO and mechanical ventilation within 36 hr of transplantation. CONCLUSIONS: Prophylactic-inhaled NO does not prevent RI in human lung transplantation. However, inhaled NO, started at reperfusion, improves gas exchange and reduces pulmonary artery pressure in those patients who develop RI.

Administration, Inhalation↗
PubMed2001

The cAMP-protein kinase A signal transduction pathway modulates ethanol consumption and sedative effects of ethanol.

Ethanol and other drugs of abuse modulate cAMP-PKA signaling within the mesolimbic reward pathway. To understand the role of the cAMP-PKA signal transduction in mediating the effects of ethanol, we have studied ethanol consumption and the sedative effects of ethanol in three lines of genetically modified mice. We report that mice with the targeted disruption of one Gsalpha allele as well as mice with reduced neuronal PKA activity have decreased alcohol consumption compared with their wild-type littermates. Genetic reduction of cAMP-PKA signaling also makes mice more sensitive to the sedative effects of ethanol, although plasma ethanol concentrations are unaffected. In contrast, mice with increased adenylyl cyclase activity resulting from the transgenic expression of a constitutively active form of Gsalpha in neurons within the forebrain are less sensitive to the sedative effects of ethanol. Thus, the cAMP-PKA signal transduction pathway is critical in modulating sensitivity to the sedative effects of ethanol as well as influencing alcohol consumption.

Adenylyl Cyclases↗
PubMed2001

Chemoprevention of breast cancer. A joint guideline from the Canadian Task Force on Preventive Health Care and the Canadian Breast Cancer Initiative's Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer.

OBJECTIVE: To assist women and their physicians in making decisions regarding the prevention of breast cancer with tamoxifen and raloxifene. EVIDENCE: Systematic review of English-language literature published from 1966 to August 2000 retrieved from MEDLINE, HealthSTAR, Current Contents and Cochrane Library. VALUES: The strength of evidence was evaluated using the methods of the Canadian Task Force on Preventive Health Care and the Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. RECOMMENDATIONS: Women at low or normal risk of breast cancer (Gail risk assessment index < 1.66% at 5 years): There is fair evidence to recommend against the use of tamoxifen to reduce the risk of breast cancer in women at low or normal risk of the disease (grade D recommendation). Women at higher risk of breast cancer (Gail index > or = 1.66% at 5 years): Evidence supports counselling women at high risk on the potential benefits and harms of breast cancer prevention with tamoxifen (grade B recommendation). The cutoff for defining high risk is arbitrary, but the National Surgical Adjuvant Breast and Bowel Project P-1 Study included women with a 5-year projected risk of at least 1.66% according to the Gail index, and the average risk of patients entered in the trial was 3.2%. Examples of high-risk clinical situations are 2 first-degree relatives with breast cancer, a history of lobular carcinoma in situ or a history of atypical hyperplasia. As the risk of breast cancer increases above 5% and the benefits outweigh the harms, a woman may choose to take tamoxifen. The duration of tamoxifen use in such situations is 5 years based on the results from trials of tamoxifen involving women with early breast cancer. If a woman raises concerns or has already been evaluated and is calculated to be at high risk, then individuals experienced and skilled in counselling may discuss the potential benefits and harms of tamoxifen use. Important additional issues: Prevention of breast cancer with raloxifene: Current evidence does not support recommending chemoprevention of breast cancer with raloxifene outside of a clinical trial setting. Screening using the Gail risk assessment index: This index was the main eligibility criterion for enrolling women in the one study that showed potential benefit from chemoprevention. However, it has not been evaluated for use as a routine screening or case-finding instrument; validation of the index is required. Overall, current evidence does not support a shift to its routine use in physicians' offices for screening or case finding. However, when a woman or her physician is concerned about the woman's increased risk of breast cancer, the index can be a useful tool in deciding whether to pursue an in-depth discussion of the potential benefits and harms of chemoprevention. Hence, the approach to identifying women at higher risk who warrant counselling and shared decision-making will vary across practices. (The risk assessment index is available online at http://bcra.nci.nih.gov/brc/). [A patient version of these guidelines appears in Appendix 2.] VALIDATION: The authors' original text was revised by both the Canadian Task Force on Preventive Health Care and the Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. The final document reflects a consensus of these contributors. SPONSOR: Health Canada. COMPLETION DATE: February 2001.

Adult↗
PubMed2001

Baseline staging tests in primary breast cancer: a practice guideline.

BACKGROUND: Breast cancer develops in over 7000 women each year in Ontario. These patients will all undergo some staging work-up at diagnosis. The Breast Cancer Disease Site Group of the Cancer Care Ontario Practice Guidelines Initiative reviewed the evidence and indications for routine bone scanning, liver ultrasonography and chest radiography in asymptomatic women who have undergone surgery for breast cancer. METHODS: A systematic review of the published literature was combined with a consensus interpretation of the evidence in the context of conventional practice. RESULTS: There were 11 studies of bone scanning reported between 1972 and 1980, involving a total of 1307 women; bone scans detected skeletal metastases in 6.8% of those with stage I breast cancer, 8.8% with stage II and 24.5% with stage III. A total of 5407 women participated in 9 studies of bone scanning reported between 1985 and 1995; in these studies, bone scans detected skeletal metastases in only 0.5% of women with stage I disease, 2.4% with stage II and 8.3% with stage III. Among 1625 women in 4 studies of liver ultrasonography reported between 1988 and 1993, hepatic metastases were detected in 0% of patients with stage I disease, 0.4% with stage II and 2.0% with stage III. Among 3884 patients in 2 studies of chest radiography published in 1988 and 1991, lung metastases were detected in 0.1% of those with stage I, 0.2% with stage II and 1.7% with stage III. False-positive rates ranged from 10% to 22% for bone scanning, 33% to 66% for liver ultrasonography and 0% to 23% for chest radiography. The false-negative rate for bone scanning was about 10%. RECOMMENDATIONS: The following recommendations apply to women with newly diagnosed breast cancer who have undergone surgical resection and who have no symptoms, physical signs or biochemical evidence of metastases. Routine bone scanning, liver ultrasonography and chest radiography are not indicated before surgery. In women with intraductal and pathological stage I tumours, routine bone scanning, liver ultrasonography and chest radiography are not indicated as part of baseline staging. In women who have pathological stage II tumours, a postoperative bone scan is recommended as part of baseline staging. Routine liver ultrasonography and chest radiography are not indicated in this group but could be considered for patients with 4 or more positive lymph nodes. In women with pathological stage III tumours, bone scanning, liver ultrasonography and chest radiography are recommended postoperatively as part of baseline staging. In women for whom treatment options are restricted to tamoxifen or hormone therapy, or for whom no further treatment is indicated because of age or other factors, routine bone scanning, liver ultrasonography and chest radiography are not indicated as part of baseline staging.

Bone Neoplasms↗
PubMed2001

Herpes simplex virus 1 ICP27 is required for transcription of two viral late (gamma 2) genes in infected cells.

The herpes simplex virus infected cell protein 27 (ICP27) is required for the expression of certain early viral proteins and for many late proteins during productive infection. Expression of at least one late (gamma 2) gene, that encoding glycoprotein C, is severely restricted in the absence of functional ICP27. The exact mode of action by which ICP27 induces late gene expression is not known, but the effect is apparent at the mRNA level as demonstrated by Northern blot analysis. To determine whether ICP27 activates late genes via transcriptional or posttranscriptional mechanisms, we initially used nuclear run-on assays to measure transcription of viral genes in Vero cells infected with wild-type (WT) virus or an ICP27 nonsense mutant virus, n504. We observed a 4-fold reduction in the nuclear run-on signal from the coding strand of the gC gene for n504-infected cells compared to that of WT-infected cells. However, interpretation of the results was complicated by the observation of a significant signal from the noncoding strand in these experiments. To obviate the problem of symmetrical transcription, we utilized in vivo RNA pulse-labeling to measure the amount of transcription of viral genes in cells infected with either WT virus or n504 virus. We found a 5- to 10-fold reduction in the transcription of the gC and U(L)47 genes, two late genes, in cells infected with n504 compared to that in cells infected with WT virus. In contrast, transcription of the ICP8 gene, an early gene, was similar in WT and n504 virus-infected cells. We also examined the stability of the gC and U(L)47 gene transcripts in n504-infected cells, and we found it to be comparable to that in WT virus-infected cells, further supporting an effect on transcription. Transcription of the gC and U(L)47 genes by n504 was normal in a cell line that expresses WT ICP27. From these results we conclude that ICP27 is required for transcription of the late gC and U(L)47 genes during productive infection.

Animals↗
PubMed2001

Local action of long-range repressors in the Drosophila embryo.

Previous studies have identified two corepressors in the early Drosophila embryo: Groucho and dCTBP: Both proteins are recruited to the DNA template by interacting with short peptide motifs conserved in a variety of sequence-specific transcriptional repressors. Once bound to DNA, Groucho appears to mediate long-range repression, while dCtBP directs short-range repression. The short-range Krüppel repressor was converted into a long-range repressor by replacing the dCtBP interaction motif (PxDLSxH) with a Groucho motif (WRPW). The resulting chimeric repressor causes a different mutant phenotype from that of the native Krüppel protein when misexpressed in transgenic embryos. The different patterning activities can be explained on the basis of long-range silencing within the hairy 5' regulatory region. The analysis of a variety of synthetic transgenes provides evidence that Groucho-dependent long-range repressors do not always cause the dominant silencing of linked enhancers within a complex cis-regulatory region. We suggest a "hot chromatin" model, whereby repressors require activators to bind DNA.

Alcohol Oxidoreductases↗
PubMed2001

Mild head injury, anticoagulants, and risk of intracranial injury.

We studied intracranial damage in patients with mild head injuries who were taking warfarin. Of the 215,785 individuals who visited the Mount Auburn and Beth Israel accident and emergency departments during our study, we identified records for 144 patients by anticoagulation status and computed tomography (CT) imaging. We retrospectively reviewed these patients and ten (7%, 95% CI 3-11) with clinically important injuries on cranial CT. Our findings suggest that patients with head injuries who receive anticoagulants have a similar or greater risk of intracranlal injury to those falling into a previously defined moderate-risk category, invalidating a previous conclusion that CT scanning is unnecessary in such patients.

Aged↗
PubMed2001

The management of hypertension in Canada: a review of current guidelines, their shortcomings and implications for the future.

Clinicians are exposed to numerous hypertension guidelines. However, their enthusiasm for these guidelines, and the impact of the guidelines, appears modest at best. Barriers to the successful implementation of a guideline can be identified at the level of the clinician, the patient or the practice setting; however, the shortcomings of the guidelines themselves have received little attention. In this paper, we review the hypertension guidelines that are most commonly encountered by Canadian clinicians: the "1999 Canadian Recommendations for the Management of Hypertension," "The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure" in the United States and the "1999 World Health Organization-International Society of Hypertension Guidelines for the Management of Hypertension." The key points of these guidelines are compared and the shortcomings that may impede their ability to influence practice are discussed. The main implications for future guideline developers are outlined.

Antihypertensive Agents↗
PubMed2001

Brinker is a sequence-specific transcriptional repressor in the Drosophila embryo.

A Dpp activity gradient specifies multiple thresholds of gene expression in the dorsal ectoderm of the early embryo. Some of these thresholds depend on a putative repressor, Brinker, which is expressed in the neurogenic ectoderm in response to the maternal Dorsal gradient and Dpp signaling. Here we show that Brinker is a sequence-specific transcriptional repressor. It binds the consensus sequence, TGGCGc/tc/t, and interacts with the Groucho corepressor through a conserved sequence motif, FKPY. An optimal Brinker binding site is contained within an 800-bp enhancer from the tolloid gene, which has been identified as a genetic target of the Brinker repressor. A tolloid-lacZ transgene containing point mutations in this site exhibits an expanded pattern of expression, suggesting that Brinker directly represses tolloid transcription. We discuss other examples of transcriptional repressors constraining the activities of signaling pathways.

Amino Acid Motifs↗