Procarbazine, lomustine and vincristine toxicity in low-grade gliomas.

BACKGROUND: Procarbazine, lomustine, and vincristine (pcv) significantly improve survival outcomes in lgg (low-grade gliomas). Administration of pcv to lgg patients increased tremendously over the past years as it went from 2 patients per year between 2005 and 2012 to 23 patients in 2015 only in our centre. However, serious hematological and non-hematological adverse events may occur. The purpose of this study was to evaluate the toxicity of pcv and its clinical relevance in our practice. METHODS: We retrospectively reviewed the charts of 57 patients with lgg who received pcv at the Centre hospitalier de l'Université de Montréal between 1 January 2005 and 27 July 2016. RESULTS: Procarbazine, lomustine, and vincristine were associated with severe hematological toxicity as clinically significant grade 3 anemia, neutropenia, and thrombocytopenia occurred in 7%, 10%, and 28% of patients, respectively. Other frequent adverse events such as the increase of liver enzymes, cutaneous rash, neurotoxicity, and vomiting occurred in 65%, 26%, 60%, and 40% of patients, respectively. Patients with prophylactic trimethoprim/sulfamethoxazole had more grade 3 hematological toxicity with pcv, especially anemia (p = 0.040) and thrombocytopenia (p = 0.003) but we found no increase in pcv toxicity in patients on concurrent anticonvulsants. Patients with grade 3 neutropenia had a significantly lower survival (median survival 44.0 months vs. 114.0 months, p = 0.001). Patients who were given pcv at diagnosis had more grade 3 anemia than those who received it at subsequent lines of treatment (p = 0.042). CONCLUSION: Procarbazine, lomustine, and vincristine increase survival in lgg but were also associated with major hematologic, hepatic, neurologic, and cutaneous toxicity. Anti-Pneumocystis jiroveci pneumonia (pjp) prophylaxis, but not anticonvulsants, enhances hematologic toxicity.

Genetic and physical interactions between Srp1p and nuclear pore complex proteins Nup1p and Nup2p.

Nup1p is a yeast nuclear pore complex protein (nucleoporin) required for nuclear protein import, mRNA export and maintenance of normal nuclear architecture. We have used a genetic approach to identify other proteins that interact functionally with Nup1p. Here we describe the isolation of seventeen mutants that confer a requirement for Nup1p in a background in which this protein is normally not essential. Some of the mutants require wild-type Nup1p, while others are viable in combination with specific nup1 alleles. Several of the mutants show nonallelic noncomplementation, suggesting that the products may be part of a hetero-oligomeric complex. One is allelic to srp1 which, although it was identified in an unrelated screen, was shown to encode a protein that is localized to the nuclear envelope (Yano, R., M. Oakes, M. Yamaghishi, J. A. Dodd, and M. Nomura. 1992. Mol. Cell. Biol. 12:5640-5651). We have used immunoprecipitation and fusion protein precipitation to show that Srp1p forms distinct complexes with both Nup1p and the related nucleoporin Nup2p, indicating that Srp1p is a component of the nuclear pore complex. The distant sequence similarity between Srp1p and the beta-catenin/desmoplakin family, coupled with the altered structure of the nuclear envelope in nup1 mutants, suggests that Srp1p may function in attachment of the nuclear pore complex to an underlying nuclear skeleton.

Polarity: the role of localized secretion.

Studies of single cells from brown algae suggest that localized secretions stabilize the polar axis resulting in an asymmetry in the cell wall. This cortical asymmetry appears to play a role in orienting the plane of cell division and in determining the different fates of the resulting daughter cells. Recent studies indicate that similar processes may operate in seed plants.

Incorporation of iododeoxyuridine into DNA of granulocytes in patients.

Iododeoxyuridine (IdUrd) competes with thymidine for incorporation into DNA. In order to measure the incorporation of the drug in vivo, granulocytes were isolated from peripheral blood of patients at various times during and after 9- to 14-day IdUrd i.v. continuous infusions. DNA was extracted and enzymatically hydrolyzed. Both thymidine and IdUrd were separated and measured by high-performance liquid chromatography. Thymidine substitution by IdUrd was less than 1% prior to the fifth day of infusion and then increased rapidly to achieve a maximal value between 7 and 17% at the end of the infusion. In our protocol, thrombocytopenia was the most frequent dose-limiting systemic toxicity. For our group of patients, there was a clear overall relationship between the extent of substitution by IdUrd and the hematological toxicity. To our knowledge, these data provide the first direct quantitative determination of substitution by a drug into DNA in vivo without the use of radiolabeled compounds. The ability to directly monitor drug incorporation into DNA may provide the basis for monitoring and improving the selectivity of therapy.

Fluorodeoxyuridine modulation of the incorporation of iododeoxyuridine into DNA of granulocytes: a phase I and clinical pharmacological study.

The amount of iododeoxyuridine (IdUrd) incorporated into DNA determines the degree of radiosensitization. Fluorodeoxyuridine (FdUrd) has been shown to biochemically modulate IdUrd incorporation into DNA in vitro and in vivo. In this Phase I study, these drugs were coadministered to patients during 14-day continuous i.v. infusion periods in order to investigate whether the incorporation of IdUrd into DNA in vivo could be increased without increasing the dose of IdUrd. IdUrd plasma concentrations and incorporation of IdUrd into DNA of granulocytes were measured by high-performance liquid chromatography. Up to 8.8% substitution of thymidine by IdUrd was observed. Even at 3.5 mg/m2/day FdUrd for 14 days (78% of the maximum-tolerated dose as a single agent), no clinically relevant enhancement of incorporation of IdUrd into DNA of granulocytes was observed. Also, no changes in plasma levels of IdUrd were observed with escalating doses of FdUrd. Toxicity patterns (stomatitis, diarrhea, and bone marrow depression) and isobologram analysis suggested that IdUrd and FdUrd had additive, rather than synergistic, effects.

Phase II study of troxacitabine (BCH-4556) in patients with advanced and/or metastatic renal cell carcinoma: a trial of the National Cancer Institute of Canada-Clinical Trials Group.

PURPOSE: A multi-institution phase II study was undertaken by National Cancer Institute of Canada-Clinical Trials Group to evaluate the efficacy and toxicity of intravenous troxacitabine (Troxatyl; Shire Pharmaceuticals Plc, Laval, Quebec, Canada), in patients with renal cell carcinoma. PATIENTS AND METHODS: Between June 1999 and March 2000, 35 patients (24 male) with a mean age of 60 years who had advanced and/or metastatic disease were treated with troxacitabine given as an intravenous infusion over 30 minutes at a dose of 10 mg/m2 intravenously, once every 3 weeks. RESULTS: Of the 33 of 35 patients evaluable for response, there were two confirmed partial responses, 21 patients had stable disease (median duration, 4.4 months), and 10 patients had progressive disease. Eight patients remained stable for more than 6 months, of whom six remain free of progression. The most common drug-related nonhematologic toxicities observed were skin rash (77.1%), hand-foot syndrome (68.6%), alopecia (51.4%), fatigue (51.4%), and nausea (57.1%). Out of a total of 145 cycles of treatment, 98 were given without steroid premedication, whereas 47 cycles were given with steroid premedication. Without premedication, skin rash occurred in 37% of cycles compared with 26% when steroids were given prophylactically. CONCLUSION: Troxacitabine given at a dose of 10 mg/m2 once every 3 weeks was well tolerated in patients with metastatic renal cell cancer, with common toxicities being a moderate to severe granulocytopenia and skin rash. Steroid premedication may reduce the frequency and severity of the skin rash. Our current study suggests that the nucleoside analog troxacitabine may have modest activity against renal cell carcinoma; however, larger studies are required to confirm this.

Two types of recombination hotspots in bacteriophage T4: one requires DNA damage and a replication origin and the other does not.

Recombination hotspots have previously been discovered in bacteriophage T4 by two different approaches, marker rescue recombination from heavily damaged phage genomes and recombination during co-infection by two undamaged phage genomes. The phage replication origin ori(34) is located in a region that has a hotspot in both assays. To determine the relationship between the origin and the two kinds of hotspots, we generated phage carrying point mutations that should inactivate ori(34) but not affect the gene 34 reading frame (within which ori(34) is located). The mutations eliminated the function of the origin, as judged by both autonomous replication of plasmids during T4 infection and two-dimensional gel analysis of phage genomic replication intermediates. As expected from past studies, the ori(34) mutations also eliminated the hotspot for marker rescue recombination from UV-irradiated genomes. However, the origin mutations had no effect on the recombination hotspot that is observed with co-infecting undamaged phage genomes, demonstrating that some DNA sequence other than the origin is responsible for inflated recombination between undamaged genomes. The hotspots for marker rescue recombination may result from a replication fork restart process that acts upon origin-initiated replication forks that become blocked at nearby DNA damage. The two-dimensional gel analysis also revealed phage T4 replication intermediates not previously detected by this method, including origin theta forms.

Selective incorporation of iododeoxyuridine into DNA of hepatic metastases versus normal human liver.

Fourteen patients received 5-iodo-2(1)-deoxyuridine (IdUrd) before surgery for placement of a hepatic arterial catheter. Biopsy specimens were obtained at the time of surgery and incorporation of IdUrd into deoxyribonucleic acid (DNA) in tumor and normal hepatic tissue was measured by HPLC and used as an index of drug selectivity. Over a 3-day intravenous infusion of IdUrd at 1000 mg/m2/day, substitution for thymidine in tumor DNA averaged 3.1%. Normal hepatic DNA contained less than 1% substitution by IdUrd. Arterial delivery of IdUrd increased levels in DNA, whereas modulation with fluorodeoxyuridine produced mixed results. In six patients, flow cytometric analysis showed that the tumor contained a median of 32% of tumor cells that had incorporated IdUrd in 3 days, corresponding to a potential doubling time of only 10 days. Thymidylate synthetase activity in tumors was 20-fold greater than in normal liver tissue, whereas thymidine kinase activity was twofold greater in tumors. These pharmacologic studies encourage further clinical trials of IdUrd as a cytotoxic agent or radiosensitizer.

The importance of dose scheduling with mitoxantrone, 5-fluorouracil and leucovorin in metastatic breast cancer.

We have studied a mitoxantrone, 5-fluorouracil (5-FU) and leucovorin chemotherapy regimen in metastatic breast cancer. 8 patients received mitoxantrone 10 mg/m2 on day 1, leucovorin 200 mg/m2 and 5-FU 300 mg/m2 on days 1-5 by intravenous bolus every 28 days in a pilot study. Grades 3-4 granulocytopenia followed 55% of the courses, with 2 patients admitted for febrile neutropenia. Only a 29% objective response rate was seen in a subsequent phase II trial using reduced mitoxantrone doses. Comparison with other trials suggested that 5-day bolus 5-FU administration adversely affects the combination's therapeutic index.

Iododeoxyuridine (IdUrd) incorporation into DNA of human hematopoietic cells, normal liver and hepatic metastases in man: as a radiosensitizer and as a marker for cell kinetic studies.

Iododeoxyuridine (IdUrd) was administered as a continuous infusion for 14 days to patients with glioblastoma and sarcoma, and for 3 days to patients with metastatic colorectal carcinoma. In the first group, the maximum incorporation of IdUrd into DNA was determined, taking granulocytes as parameter. In the second group, selective incorporation into DNA of normal liver and hepatic metastases of colorectal cancer was investigated. The highest dose of 675 mg/sq.m./day for 14 days produced IdUrd plasma concentrations of 1.8 +/- 0.3 microM, and a substitution of dThd by IdUrd in the range of 7.1-11.7%. Coadministration of fluorodeoxyuridine did not show significant enhancement of IdUrd-incorporation in granulocytes. Three-day intravenous infusions of IdUrd 1000 mg/sq.m./day produced 1.7-4.5% IdUrd-incorporation in hepatic metastases. Three-day intraarterial infusions (hepatic artery) produced 3.8-10.5% dThd-replacement, whereas, in 9/10 patients this was less than 1% in normal liver. In tumor tissue there was a trend towards FdUrd-modulated enhancement of IdUrd-incorporation, although there was considerable scatter. Cell kinetic studies revealed that IdUrd-incorporation in monocytes and granulocytes was very similar. In lymphocytes, a much lower fraction incorporated IdUrd. Liver tumor contained a considerably higher fraction of IdUrd-labeled cells, compared with normal liver. Potential doubling times for the tumors were estimated to be 10 days.

Functional characteristics of mature granulocytes in a patient with acute promyelocytic leukemia treated with all-trans retinoic acid.

All-trans retinoic acid (ATRA) is a differentiating agent that has been successfully used in the treatment of patients with acute promyelocytic leukemia (APL). Functional properties of peripheral blood neutrophils from a patient with APL during treatment with ATRA have been studied. Wright stain of patient neutrophils showed hypogranulation and loose nuclear chromatin when compared with normal neutrophils. These cells were of lower density than normal neutrophils and separated on density gradient centrifugation with mononuclear cells. Surface antigen expression by FACS distinguished these cells from lymphocytes. The histograms showed a population of larger cells expressing CD18 and CD11b, distinct from the smaller cells which did not express CD11b. fMLP caused an increase in intracellular calcium (measured spectrophotometrically) that was inhibited by the calcium chelator BAPTA. Actin polymerization following cell activation was measured using NBD-phallacidin staining and FACS. Both IL-8 and fMLP caused rapid increases using F-actin content (2.5-3.0 fold), which were of greater magnitude than generally seen with normal neutrophils. Treatment with BAPTA before activation with fMLP did not blunt the actin responses, despite complete inhibition of an intracellular calcium increase. In summary, neutrophils derives from differentiated APL cells express CD18/CD11b, and exhibit a similar degree of actin polymerization in response to fMLP and IL-8, independent of an increase in intracellular calcium. Although the actin responses are greater than normal neutrophils, most properties are similar, supporting the contention that these cells can protect the host. The exaggerated actin response to inflammatory mediators, however, may play a role in the 'retinoic acid syndrome'.

Functional properties of HL60 cells matured with all-trans-retinoic acid and DMSO: differences in response to interleukin-8 and fMLP.

All-trans-retinoic acid (ATRA) causes granulocyte differentiation in patients with acute promyelocytic leukemia. HL60 cells are frequently used as an in vitro model for studying granulocytes during maturation. We have previously studied actin polymerization in response to fMLP in HL60 cells undergoing DMSO induced maturation, and reported that IL-8 causes actin polymerization in neutrophils in a manner similar to fMLP. We now compare chemotaxis and actin polymerization in response to IL-8 and fMLP, and nitroblue tetrazolium (NBT) reduction in HL60 cells matured with ATRA and DMSO. Cells cultured for 4 days with ATRA and DMSO showed morphologic evidence of maturation. NBD-phallacidin staining and flow cytometry were used to measure changes in F-actin content in response to IL-8 and fMLP. Uninduced cells were not capable of actin polymerization or chemotaxis. Cells matured with ATRA exhibited a 2.6-fold increase in F-actin content in response to IL-8, but only a 1.2-fold increase in response to fMLP. Cells matured with DMSO responded to both IL-8 and fMLP in an equal manner with 1.6-fold increases in F-actin. The 2 h migration for ATRA induced cells was 124 microns in response to IL-8, 107 microns with fMLP, and 105 microns in buffer. DMSO induced cells migrated 89 microns in response to IL-8, 106 microns with fMLP, and 66 microns in buffer. With maturation, 65% of the ATRA induced cells reduced NBT compared with only 15% of the DMSO induced cells. In summary, HL60 cells cultured in ATRA develop greater functional maturity than those cultured in DMSO, and a greater responsiveness to IL-8 than fMLP, a finding distinct from previously reported work in neutrophils.

Occupationally related magnetic field exposure and male subfertility.

OBJECTIVE: To determine whether there is an association between occupationally related magnetic field exposure, as estimated in milligauss (mG), and male subfertility. DESIGN: Nested case-control study using three defined case groups and one standard control group. SETTING: Yale New Haven Hospital Infertility Clinic, New Haven, Connecticut. PATIENTS, INTERVENTIONS: Male partners of couples seeking diagnosis and care at the infertility clinic. Men included in the analysis had complete first semen analysis and interview information. Subjects for this investigation consisted of case groups for motility (n = 177), morphology (n = 135), and concentration (n = 172); controls included men normal on all three parameters (n = 304). MAIN OUTCOME MEASURES: Laboratory confirmation in semen analysis of poor morphology, inadequate motility, and low concentration. Comparisons of occupational magnetic field exposure categories are made between case groups and controls. RESULTS: The odds of high job exposure category to magnetic fields (> 3 mG [> 0.3 muT]) for morphology cases were odds ratio (OR) = 0.6, for motility cases OR = 1.1, and concentration cases OR = 1.0 as compared with controls. No significant association was demonstrated for medium exposure (> 2 to 3 mG) among all case groups. Multivariate adjustment for selected risk factors did not substantially change estimates of risk. CONCLUSIONS: A lack of association between occupationally related categories of magnetic field exposure and male subfertility, as evaluated by morphology, motility, and concentration, has been demonstrated. These findings do not substantiate theories of deleterious effects to male reproductive health from magnetic fields.

Metabolism of polynuclear aromatic hydrocarbon in human term placenta influenced by cigarette smoke exposure.

The relative contributions of biologic and environmental factors on embryo-fetal development were elucidated in a population of pregnant women who were exposed to varying amounts of active cigarette smoke and women who were not exposed to cigarette smoke. The neonatal weight at birth, placental weight at delivery, duration of pregnancy, and placental xenobiotic (polynuclear aromatic hydrocarbon, PAH) metabolism potential were assessed in this population. The overall metabolic capability in exposed and unexposed placental tissue was measured by in vitro assays using microsomes and a PAH substrate, benzo[a]pyrene (B[a]P). Toxicity potential was determined by B[a]P-metabolite-DNA adduct generation under the same incubation condition. Cigarette smoke exposure increased the overall PAH metabolism potential in placental tissues by approximately 200% (nonsmoker 176.2 +/- 33.6, n = 25; smoker 524.5 +/- 75.5, n = 32 pmol/mg protein) whereas PAH-DNA adduct formation potential did not increase significantly over the basal level (nonsmoker 5002 +/- 830, n = 15; smoker 6172 +/- 1443, n = 22 fmol B[a]P equivalent/mumol DNA/mg protein). Exposure to cigarette smoke during pregnancy is deleterious to fetal development as reflected by reduced neonatal weight at birth. In contrast, placental weight reduction is indistinct, but placentae expressed markedly augmented overall xenobiotic (PAH) metabolism capability in response to cigarette smoke exposure during pregnancy, indicating placental metabolism may be an important mediator of adverse effects induced by such xenobiotic exposure.

Canadian recommendations for the treatment of recurrent or progressive glioblastoma multiforme.

Recommendation 1: Multidisciplinary ApproachTo optimize treatment outcomes, the management of patients with recurrent glioblastoma should be individualized and should involve a multidisciplinary team approach, including neurosurgery, neuropathology, radiation oncology, neuro-oncology, and allied health professions.Recommendation 2: ImagingThe standard imaging modality for assessment of recurrent glioblastoma is Gd-enhanced magnetic resonance imaging (mri). Tumour recurrence should be assessed according to the criteria set out by the Response Assessment in Neuro-Oncology Working Group. The optimal timing and frequency of mri after chemoradiation and adjunctive therapy have not been established.Recommendation 3: Pseudo-progressionProgression observed by mri after chemoradiation can be pseudo-progression. Accordingly, treated patients should not be classified as having progressive disease by Gd-enhancing mri within the first 12 weeks after the end of radiotherapy unless new enhancement is observed outside the radiotherapy field or viable tumour is confirmed by pathology at the time of a required re-operation. Adjuvant temozolomide should be continued and follow-up imaging obtained.Recommendation 4: Repeat SurgerySurgery can play a role in providing symptom relief and confirming tumour recurrence, pseudo-progression, or radiation necrosis. However, before surgical intervention, it is essential to clearly define treatment goals and the expected impact on prognosis and the patient's quality of life. In the absence of level 1 evidence, the decision to re-operate should be made according to individual circumstances, in consultation with the multidisciplinary team and the patient.Recommendation 5: Re-irradiationRe-irradiation is seldom recommended, but can be considered in carefully selected cases of recurrent glioblastoma.Recommendation 6: Systemic TherapyClinical trials, when available, should be offered to all eligible patients. In the absence of a trial, systemic therapy, including temozolomide rechallenge or anti-angiogenic therapy, may be considered. Combination therapy is still experimental; optimal drug combinations and sequencing have not been established.

Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma.

OBJECTIVE: This analysis was performed to assess whether antiepileptic drugs (AEDs) modulate the effectiveness of temozolomide radiochemotherapy in patients with newly diagnosed glioblastoma. METHODS: The European Organization for Research and Treatment of Cancer (EORTC) 26981-22981/National Cancer Institute of Canada (NCIC) CE.3 clinical trial database of radiotherapy (RT) with or without temozolomide (TMZ) for newly diagnosed glioblastoma was examined to assess the impact of the interaction between AED use and chemoradiotherapy on survival. Data were adjusted for known prognostic factors. RESULTS: When treatment began, 175 patients (30.5%) were AED-free, 277 (48.3%) were taking any enzyme-inducing AED (EIAED) and 135 (23.4%) were taking any non-EIAED. Patients receiving valproic acid (VPA) only had more grade 3/4 thrombopenia and leukopenia than patients without an AED or patients taking an EIAED only. The overall survival (OS) of patients who were receiving an AED at baseline vs not receiving any AED was similar. Patients receiving VPA alone (97 [16.9%]) appeared to derive more survival benefit from TMZ/RT (hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.24-0.63) than patients receiving an EIAED only (252 [44%]) (HR 0.69, 95% CI 0.53-0.90) or patients not receiving any AED (HR 0.67, 95% CI 0.49-0.93). CONCLUSIONS: VPA may be preferred over an EIAED in patients with glioblastoma who require an AED during TMZ-based chemoradiotherapy. Future studies are needed to determine whether VPA increases TMZ bioavailability or acts as an inhibitor of histone deacetylases and thereby sensitizes for radiochemotherapy in vivo.

Phase I study of Aplidine in a dailyx5 one-hour infusion every 3 weeks in patients with solid tumors refractory to standard therapy. A National Cancer Institute of Canada Clinical Trials Group study: NCIC CTG IND 115.

BACKGROUND: Aplidine is a cyclic depsipeptide isolated from the marine tunicate Aplidium albicans. METHODS: This phase I study of Aplidine given as a 1-hour i.v. infusion daily for 5 days every 3 weeks was conducted in patients with refractory solid tumors. Objectives were to define the dose limiting toxicities, the maximal tolerated dose, and the recommended phase II dose. RESULTS: Thirty-seven patients were accrued on study. Doses ranged from 80 microg/m(2) to 1500 microg/m(2)/day. Eleven patients received more than three cycles of Aplidine. Dose-limiting toxicities occurred at 1500 microg/m(2) and 1350 microg/m(2)/day and consisted of nausea, vomiting, myalgia, fatigue, skin rash and diarrhea. Mild to moderate muscular pain and weakness was noted in patients treated with multiple cycles with no significant drug related neurotoxicity. Bone marrow toxicity was not observed. The recommended dose for phase II studies was 1200 microg/m(2) daily for 5 days, every 3 weeks. Pharmacokinetic studies performed during the first cycle demonstrated that therapeutic plasma levels of Aplidine are reachable well below the recommended dose. Nine patients with progressive disease at study entry had stable disease and two had minor responses, one in non-small cell lung cancer and one in colorectal cancer. CONCLUSIONS: Aplidine given at a dose of 1200 microg/m(2) daily for 5 days, every 3 weeks is well tolerated with few severe adverse events. This schedule of Aplidine is under evaluation in phase II studies in hematological malignancies and solid tumors.

Bacteriophage T4 initiates bidirectional DNA replication through a two-step process.

Two-dimensional gel analysis of the bacteriophage T4 ori(uvsY) region revealed a novel "comet" on the Y arc. This comet contains simple Y molecules in which the branch points map to the ori(uvsY) transcript region. The comet depends on the the origin and DNA synthesis and is abolished by a mutation that reduces replication without affecting transcription. These results argue that the branched molecules are intermediates in replication initiation. A transcriptional terminator, cloned just downstream of the origin promoter, shortened the tail of the comet. Therefore, the location of the transcript determines the DNA branch points. We conclude that the comet DNA consists of intermediates in which unidirectional replication has been triggered by priming from the RNA of the origin R loop.

Ultrasonographic assessment of gestational age with the distal femoral and proximal tibial ossification centers in the third trimester.

A prospective sonographic evaluation of the distal femoral and proximal tibial epiphyseal ossification centers in 228 normal pregnant women was carried out from 28 to 40 weeks' gestation. The mean gestational age at which the distal femoral epiphysis and proximal tibial epiphysis were imaged was 34 and 38 weeks, respectively. The distal femoral epiphysis was not identifiable before 28 weeks but was observed in 72% of fetuses at 33 weeks and in 94% of fetuses at 34 weeks' gestation. The presence of a distal femoral epiphysis measuring 1 or 2 mm was associated with a gestational age of greater than 33 weeks in 87.0% of fetuses, whereas a distal femoral epiphysis measuring greater than or equal to 3 mm was associated with a gestational age greater than 37 weeks in 85% of fetuses. The proximal tibial epiphysis, which was absent before 34 weeks' gestation, was observed in 56% of fetuses at 36 weeks, in 80% of fetuses at 37 weeks, and in 100% of fetuses at 39 weeks of gestation. The presence of a proximal tibial epiphysis of 1 or 2 mm was associated with a gestational age of greater than 36 weeks in 88% of fetuses, whereas a proximal tibial epiphysis greater than or equal to 3 mm was associated with a gestational age of greater than 38 weeks in 94% of fetuses. The sonographic evaluation of distal femoral epiphysis/proximal tibial epiphysis can be used as independent markers for estimation of gestational age during the third trimester, a period in which standard fetal biometric estimates of gestational age are least accurate.

Human exposure to magnetic fields: a comparative assessment of two dosimeters.

Two types of dosimeters for measuring human exposure to 60 Hz magnetic fields were compared. Fifty adults wore the single-axis, wrist model AMEX (average magnetic field exposure system) and the triple axis, hip-pocket or pouch model AMEX-3D meters for 2 days. Ninety-six percent of the tests were accomplished without apparent dosimeter failure. The average root mean square magnetic flux density measurements with the AMEX-3D (mean = 0.10 microT, S.D. = 0.07, range = 0.03-0.31) were significantly higher than with the AMEX meter (mean = 0.07 microT, S.D. 0.05, range = 0.02-0.27 microT) (t test, P < 0.01). There was substantial correlation between the AMEX and the AMEX-3D measurements (Pearson's correlation coefficient = 0.65, P < 0.01) but poor concordance (Intraclass correlation coefficient = -0.25). These results suggest that there is a wide variation in exposure to extremely low frequency magnetic fields in the population. Magnetic field measurements with the AMEX-3D are nearly always higher than with the AMEX dosimeters. Caution is advised when comparing magnetic field measurements made with different types of dosimeters.