We recently reported the purification of a lymphocyte granule protein called "fragmentin," which was identified as a serine protease with the ability to induce oligonucleosomal DNA fragmentation and apoptosis (Shi, L., R. P. Kraut, R. Aebersold, and A. H. Greenberg. 1992. J. Exp. Med. 175:553). We have now purified two additional proteases with fragmentin activity from lymphocyte granules. The three proteases are of two types; one has the unusual ability to cleave a tripeptide thiobenzyl ester substrate after aspartic acid, similar to murine cytotoxic cell protease I/granzyme B, while two are tryptase-like, preferentially hydrolyzing after arginine, and bear some homology to human T cell granule tryptases, granzyme 3, and Hanukah factor/granzyme A. Using tripeptide chloromethyl ketones, the pattern of inhibition of DNA fragmentation corresponded to the inhibition of peptide hydrolysis. The Asp-ase fragmentin was blocked by aspartic acid-containing tripeptide chloromethyl ketones, while the tryptase fragmentins were inhibited by arginine-containing chloromethyl ketones. The two tryptase fragmentins were slow acting and were partly suppressed by blocking proteins synthesis with cycloheximide in the YAC-1 target cell. In contrast, the Asp-ase fragmentin was fast acting and produced DNA damage in the absence of protein synthesis. Using a panel of unrelated target cells of lymphoma, thymoma, and melanoma origin, distinct patterns of sensitivity to the three fragmentins were observed. Thus, these three granule proteases make up a family of fragmentins that activate DNA fragmentation and apoptosis by acting on unique substrates in different target cells.

We used a restriction endonuclease to analyze the beta-thalassemia gene in Sardinia. When we digested human DNA with the restriction enzyme Bam HI, the beta-globin gene split into a 5' portion contained in a fragment of DNA 1.8 kb in length and a 3' portion in a fragment 9.3 kb in length. In some subjects, a variation in the nucleotide sequence affecting the site recognized by this enzyme on the 3' side of the beta-globin gene resulted in a different fragment, 22 kb in length, which contained the 3' portion of the beta-globin gene. In Sardinians without beta-thalassemia, the frequency of the 9.3-kb fragment was 0.67, and that of the 22-kb fragment was 0.33. In contrast, all the beta 0-thalassemia genes were associated exclusively with the 9.3-kb fragment. Thus, the beta 0-thalassemia lesion in Sardinians apparently arose on a chromosome that had the 9.3-kb Bam HI fragment. This observation can be used in prenatal diagnosis of beta 0-thalassemia in Sardina, since demonstration of the 22.0-kb fragment would indicate the normal beta-globin genotype and exclude the beta 0-thalassemia lesion on that chromosome. (N Engl J Med 302:185-188, 1980).

BACKGROUND

Abiraterone acetate, an androgen biosynthesis inhibitor, improves overall survival in patients with metastatic castration-resistant prostate cancer after chemotherapy. We evaluated this agent in patients who had not received previous chemotherapy.

METHODS

In this double-blind study, we randomly assigned 1088 patients to receive abiraterone acetate (1000 mg) plus prednisone (5mg twice daily) or placebo plus prednisone. The coprimary end points were radiographic progression-free survival and overall survival.

RESULTS

The study was unblinded after a planned interim analysis that was performed after 43% of the expected deaths had occurred. The median radiographic progression-free survival was 16.5 months with abiraterone-prednisone and 8.3 months with prednisone alone (hazard ratio for abiraterone-prednisone vs. prednisone alone, 0.53; 95% confidence interval [CI], 0.45 to 0.62; P<0.001). Over a median follow-up period of 22.2 months, overall survival was improved with abiraterone-prednisone (median not reached, vs. 27.2 months for prednisone alone; hazard ratio, 0.75; 95% CI, 0.61 to 0.93; P = 0.01) but did not cross the efficacy boundary. Abiraterone-prednisone showed superiority over prednisone alone with respect to time to initiation of cytotoxic chemotherapy, opiate use for cancer-related pain, prostate-specific antigen progression, and decline in performance status. Grade 3 or 4 mineralocorticoid-related adverse events and abnormalities on liver-function testing were more common with abiraterone-prednisone.

CONCLUSIONS

Abiraterone improved radiographic progression-free survival, showed a trend toward improved overall survival, and significantly delayed clinical decline and initiation of chemotherapy in patients with metastatic castration-resistant prostate cancer.

Vessel size imaging is a new method that is based on simultaneous measurement of the changes Delta R(2) and Delta R(2)(*) in relaxation rate constants induced by the injection of an intravascular superparamagnetic contrast agent. Using the static dephasing approximation for Delta R(2)(*) estimation and the slow-diffusion approximation for Delta R(2) estimation, it is shown that the ratio Delta R(2)/Delta R(2)(*) can be expressed as a function of the susceptibility difference between vessels and brain tissue, the brain water diffusion coefficient, and a weighted mean of vessel sizes. Comparison of the results with 1) the Monte Carlo simulations used to quantify the relationship between tissue parameters and susceptibility contrast, 2) the experimental MRI data in the normal rat brain, and 3) the histologic data establishes the validity of this approach. This technique, which allows images of a weighted mean of the vessel size to be obtained, could be useful for in vivo studies of tumor vascularization. Magn Reson Med 45:397-408, 2001.

To assess the rate-limiting step in muscle glycogen synthesis in non-insulin-dependent diabetes mellitus (NIDDM), the concentration of glucose-6-phosphate (G6P) was measured by 31P nuclear magnetic resonance (NMR) during a hyperglycemic-hyperinsulinemic clamp. Six subjects with NIDDM and six age weight-matched controls were studied at similar steady-state plasma concentrations of insulin (approximately 450 pmol/liter) and glucose (11 mmol/liter). The concentration of G6P in the gastrocnemius muscle was measured by 31P NMR. Whole-body oxidative and nonoxidative glucose metabolism was determined by the insulin-glucose clamp technique in conjunction with indirect calorimetry. Nonoxidative glucose metabolism which under these conditions is a measure of muscle glycogen synthesis (1990. N. Engl. J. Med. 322:223-228), was 31 +/- 7 mumol/(kg body wt-min) in the normal subjects and 13 +/- 3 mumol/(kg body wt-min) in the NIDDM subjects (P less than 0.05). The concentration of G6P was higher (0.24 +/- 0.02 mmol/kg muscle) in the normal subjects than in the NIDDM subjects (0.17 +/- 0.02, P less than 0.01). Increasing insulin concentrations to insulin 8,500 pmol/liter in four NIDDM subjects restored the glucose uptake rate and G6P concentrations to normal levels. In conclusion, the lower concentration of G6P in the diabetic subjects despite a decreased rate of nonoxidative glucose metabolism is consistent with a defect in muscle glucose transport or phosphorylation reducing the rate of muscle glycogen synthesis.

gamma 1-Herpesviruses such as Epstein-Barr virus (EBV) have a unique ability to amplify virus loads in vivo through latent growth-transforming infection. Whether they, like alpha- and beta-herpesviruses, have been driven to actively evade immune detection of replicative (lytic) infection remains a moot point. We were prompted to readdress this question by recent work (Pudney, V.A., A.M. Leese, A.B. Rickinson, and A.D. Hislop. 2005. J. Exp. Med. 201:349-360; Ressing, M.E., S.E. Keating, D. van Leeuwen, D. Koppers-Lalic, I.Y. Pappworth, E.J.H.J. Wiertz, and M. Rowe. 2005. J. Immunol. 174:6829-6838) showing that, as EBV-infected cells move through the lytic cycle, their susceptibility to EBV-specific CD8(+) T cell recognition falls dramatically, concomitant with a reductions in transporter associated with antigen processing (TAP) function and surface human histocompatibility leukocyte antigen (HLA) class I expression. Screening of genes that are unique to EBV and closely related gamma 1-herpesviruses of Old World primates identified an early EBV lytic cycle gene, BNLF2a, which efficiently blocks antigen-specific CD8(+) T cell recognition through HLA-A-, HLA-B-, and HLA-C-restricting alleles when expressed in target cells in vitro. The small (60-amino acid) BNLF2a protein mediated its effects through interacting with the TAP complex and inhibiting both its peptide- and ATP-binding functions. Furthermore, this targeting of the major histocompatibility complex class I pathway appears to be conserved among the BNLF2a homologues of Old World primate gamma 1-herpesviruses. Thus, even the acquisition of latent cycle genes endowing unique growth-transforming ability has not liberated these agents from evolutionary pressure to evade CD8(+) T cell control over virus replicative foci.

Both balanced crystalloids and saline are used for intravenous fluid administration in critically ill adults, but it is not known which results in better clinical outcomes.

In a pragmatic, cluster-randomized, multiple-crossover trial conducted in five intensive care units at an academic center, we assigned 15,802 adults to receive saline (0.9% sodium chloride) or balanced crystalloids (lactated Ringer's solution or Plasma-Lyte A) according to the randomization of the unit to which they were admitted. The primary outcome was a major adverse kidney event within 30 days - a composite of death from any cause, new renal-replacement therapy, or persistent renal dysfunction (defined as an elevation of the creatinine level to ≥200% of baseline) - all censored at hospital discharge or 30 days, whichever occurred first.

Among the 7942 patients in the balanced-crystalloids group, 1139 (14.3%) had a major adverse kidney event, as compared with 1211 of 7860 patients (15.4%) in the saline group (marginal odds ratio, 0.91; 95% confidence interval [CI], 0.84 to 0.99; conditional odds ratio, 0.90; 95% CI, 0.82 to 0.99; P=0.04). In-hospital mortality at 30 days was 10.3% in the balanced-crystalloids group and 11.1% in the saline group (P=0.06). The incidence of new renal-replacement therapy was 2.5% and 2.9%, respectively (P=0.08), and the incidence of persistent renal dysfunction was 6.4% and 6.6%, respectively (P=0.60).

Among critically ill adults, the use of balanced crystalloids for intravenous fluid administration resulted in a lower rate of the composite outcome of death from any cause, new renal-replacement therapy, or persistent renal dysfunction than the use of saline. (Funded by the Vanderbilt Institute for Clinical and Translational Research and others; SMART-MED and SMART-SURG ClinicalTrials.gov numbers, NCT02444988 and NCT02547779 .).

The International AIDS Society-USA (IAS-USA) Drug Resistance Mutations Group reviews new data on HIV-1 drug resistance that have been published or presented at recent scientific meetings to maintain a current list of mutations associated with antiretroviral drug resistance.This December 2008 version of the IAS-USA drug resistance mutations figures updates those published in this journal in March/April 2008 (Johnson VA, Brun-Vezinet F, Clotet B, et al, Top HIV Med, 2008;16:62-68). The compilation includes mutations that may contribute to a reduced virologic response to HIV-1 drugs. It should not be assumed that the list presented here is exhaustive. Drugs that have been approved by the US Food and Drug Administration (US FDA) as well as any drugs available in expanded access programs are included and listed in alphabetical order by drug class. The figures are designed for practitioners to use in identifying key mutations associated with viral resistance to antiretroviral drugs and in making therapeutic decisions.

To learn how lipooligosaccharide (LOS) phase variations affect pathogenesis, we studied two male volunteers who were challenged intraurethrally with Neisseria gonorrhoeae that make a single LOS of 3,600 daltons and sequentially followed LOS expression by gonococci as urethritis developed. LOS variation occurred in vivo. Signs and symptoms of gonorrhea began with the appearance of variants making 4,700-dalton LOS that are immunochemically similar to glycosphingolipids of human hematopoietic cells (Mandrell, R.E., J.M. Griffiss, and B.A. Macher. 1989. J. Exp. Med. 168:107) and that have acceptors for sialic acid. A variant that appeared at the onset of leukorrhoea was shed by 34/36 men with naturally acquired gonorrhea at the time they sought medical attention; the other two shed the variant associated with dysuria. None shed the challenge variant. These data show that in vivo phase shifts to higher molecular mass LOS that mimic human cell membrane glycolipids are associated with the development of gonococcal leukorrhea.

Human beta-defensin 3 (hBD3) is a highly charged (+11) cationic host defense peptide, produced by epithelial cells and neutrophils. hBD3 retains antimicrobial activity against a broad range of pathogens, including multiresistant Staphylococcus aureus, even under high-salt conditions. Whereas antimicrobial host defense peptides are assumed to act by permeabilizing cell membranes, the transcriptional response pattern of hBD3-treated staphylococcal cells resembled that of vancomycin-treated cells (V. Sass, U. Pag, A. Tossi, G. Bierbaum, and H. G. Sahl, Int. J. Med. Microbiol. 298:619-633, 2008) and suggested that inhibition of cell wall biosynthesis is a major component of the killing process. hBD3-treated cells, inspected by transmission electron microscopy, showed localized protrusions of cytoplasmic contents, and analysis of the intracellular pool of nucleotide-activated cell wall precursors demonstrated accumulation of the final soluble precursor, UDP-MurNAc-pentapeptide. Accumulation is typically induced by antibiotics that inhibit membrane-bound steps of cell wall biosynthesis and also demonstrates that hBD3 does not impair the biosynthetic capacity of cells and does not cause gross leakage of small cytoplasmic compounds. In in vitro assays of individual membrane-associated cell wall biosynthesis reactions (MraY, MurG, FemX, and penicillin-binding protein 2 [PBP2]), hBD3 inhibited those enzymes which use the bactoprenol-bound cell wall building block lipid II as a substrate; quantitative analysis suggested that hBD3 may stoichiometrically bind to lipid II. We report that binding of hBD3 to defined, lipid II-rich sites of cell wall biosynthesis may lead to perturbation of the biosynthesis machinery, resulting in localized lesions in the cell wall as demonstrated by electron microscopy. The lesions may then allow for osmotic rupture of cells when defensins are tested under low-salt conditions.

BACKGROUND

Quality improvement (QI) programs for depressed primary care patients can improve health outcomes for 6 to 28 months; effects for longer than 28 months are unknown.

OBJECTIVE

To assess how QI for depression affects health outcomes, quality of care, and health outcome disparities at 57-month follow-up.

METHODS

A group-level randomized controlled trial.

METHODS

Forty-six primary care practices in 6 managed care organizations.

METHODS

Of 1356 primary care patients who screened positive for depression and enrolled in the trial, 991 (73%, including 451 Latinos and African Americans) completed 57-month telephone follow-up.

METHODS

Clinics were randomly assigned to usual care or to 1 of 2 QI programs supporting QI teams, provider training, nurse assessment, and patient education, plus resources to support medication management (QI-meds) or psychotherapy (QI-therapy) for 6 to 12 months.

METHODS

Probable depressive disorder in the previous 6 months, mental health-related quality of life in the previous 30 days, primary care or mental health specialty visits, counseling or antidepressant medications in the previous 6 months, and unmet need, defined as depressed but not receiving appropriate care.

RESULTS

Combined QI-meds and QI-therapy, relative to usual care, reduced the percentage of participants with probable disorder at 5 years by 6.6 percentage points (P =.04). QI-therapy improved health outcomes and reduced unmet need for appropriate care among Latinos and African Americans combined but provided few long-term benefits among whites, reducing outcome disparities related to usual care (P =.04 for QI-ethnicity interaction for probable depressive disorder).

CONCLUSIONS

Programs for QI for depressed primary care patients implemented by managed care practices can improve health outcomes 5 years after implementation and reduce health outcome disparities by markedly improving health outcomes and unmet need for appropriate care among Latinos and African Americans relative to whites; thus, equity was improved in the long run.

OBJECTIVE

Intent-to-treat analyses of the Multimodal Treatment Study of ADHD (MTA) revealed group differences on attention-deficit/hyperactivity disorder symptoms ratings, with better outcome in groups of participants who were assigned the medication algorithm-medication alone (MedMgt) and combined (Comb)--than in those who were not-behavior modification (Beh) alone and community comparison (CC). However, the effect size was reduced by 50% from the end of treatment to the first follow-up. The convergence of outcomes suggests differential changes by treatment group beween 14 and 24 months, which this report explores, both for benefits of treatment and for side effects on growth.

METHODS

We documented reported medication use at 14- and 24-month assessments and formed 4 naturalistic subgroups (Med/Med, Med/NoMed, NoMed/Med, and NoMed/NoMed). Then we performed exploratory mediator analyses to evaluate effects of changes in medication use on 14- to 24-month change scores of effectiveness (symptom ratings) and growth (height and weight measures).

RESULTS

The randomly assigned groups with the greatest improvement at the end of the treatment phase (Comb and MedMgt) deteriorated during the follow-up phase, but the other 2 groups (Beh and CC) did not. There were no significant differences in the 14- to 24-month growth rates among the randomly assigned groups, in contrast to significant growth suppression in the Comb and MedMgt at the end of the treatment phase. Changes in medication use mediated the 14- to 24-month change in attention-deficit/hyperactivity disorder symptom ratings: the subgroup that reported stopping medication (Med/NoMed) showed the largest deterioration, the subgroup that consistently reported (Med/Med) or never reported (NoMed/NoMed) medication use showed modest deterioration, and the subgroup that reported starting medication (NoMed/Med) showed improvement. Changes in medication use also mediated growth effects: the subgroup that consistently reported medication use (Med/Med) showed reduced height gain compared with the subgroup that never reported medication use (NoMed/NoMed), which actually grew faster than predicted by population norms.

CONCLUSIONS

In the MTA follow-up, exploratory naturalistic analyses suggest that consistent use of stimulant medication was associated with maintenance of effectiveness but continued mild growth suppression.

The MRI signal enhancement in a breast tumor, measured as a function of time after a bolus injection of Gd-DTPA, may contain enough information to differentiate malignant from benign tissue. We find a physiological model for measuring capillary permeability and leakage space (P. S. Tofts, A. G. Kermode, measurement of the blood-brain barrier permeability and leakage space using dynamic MR imaging. 1. Fundamental concepts. Magn. Reson. Med. 17, 357-367 (1991)) fits the data well. The enhancement curve is particularly sensitive to the preinjection T1 of the tumor, the dose, and the time of injection. This model may provide a means of characterizing the pathophysiology of breast tumors from the Gd-DTPA enhancement curve.

In a massively univariate analysis of brain image data, statistical inference is typically based on intensity or spatial extent of signals. Voxel intensity-based tests provide great sensitivity for high intensity signals, whereas cluster extent-based tests are sensitive to spatially extended signals. To benefit from the strength of both, the intensity and extent information needs to be combined. Various ways of combining voxel intensity and cluster extent are possible, and a few such combining methods have been proposed. Poline et al.'s [NeuroImage 16 (1997) 83] minimum P value approach is sensitive to signals whose either intensity or extent is significant. Bullmore et al.'s [IEEE Trans. Med. Imag. 18 (1999) 32] cluster mass method can detect signals whose intensity and extent are sufficiently large, even when they are not significant by intensity or extent alone. In this work, we study such combined inference methods using combining functions (Pesarin, F., 2001. Multivariate Permutation Tests. Wiley, New York) and permutation framework [Holmes et al., J. Cereb. Blood Flow Metab. 16 (1996) 7], which allow us to examine different ways of combining voxel intensity and cluster extent information without knowing their distribution. We also attempt to calibrate combined inference by using weighted combining functions, which adjust the test according to signals of interest. Furthermore, we propose meta-combining, a combining function of combining functions, which integrates strengths of multiple combining functions into a single statistic. We found that combined tests are able to detect signals that are not detected by voxel or cluster size test alone. We also found that the weighted combining functions can calibrate the combined test according to the signals of interest, emphasizing either intensity or extent as appropriate. Though not necessarily more sensitive than individual combining functions, the meta-combining function is sensitive to all types of signals and thus can be used as a single test summarizing all the combining functions.

Mutations at A/T bases within immunoglobulin genes have been shown to be generated by a repair pathway involving the DNA-binding moiety of the mismatch repair complex constituted by the MSH2-MSH6 proteins, together with DNA polymerase eta (pol eta). However, residual A/T mutagenesis is still observed upon inactivation in the mouse of each of these factors, suggesting that the panel of activities involved might be more complex. We reported previously (Delbos, F., A. De Smet, A. Faili, S. Aoufouchi, J.-C. Weill, and C.-A. Reynaud. 2005. J. Exp. Med. 201:1191-1196) that residual A/T mutagenesis in pol eta-deficient mice was likely contributed by another enzyme not normally involved in hypermutation, DNA polymerase kappa, which is mobilized in the absence of the normal polymerase partner. We report the complete absence of A/T mutations in MSH2-pol eta double-deficient mice, thus indicating that the residual A/T mutagenesis in MSH2-deficient mice is contributed by pol eta, now recruited by uracil N-glycosylase, the second DNA repair pathway involved in hypermutation. We propose that this particular recruitment of pol eta corresponds to a profound modification of the function of uracil glycosylase in the absence of the mismatch repair complex, suggesting that MSH2-MSH6 actively prevent uracil glycosylase from error-free repair during hypermutation. pol eta thus appears to be the sole contributor of A/T mutations in the normal physiological context.

BACKGROUND

The HELLP syndrome is a serious complication in pregnancy characterized by haemolysis, elevated liver enzymes and low platelet count occurring in 0.5 to 0.9% of all pregnancies and in 10-20% of cases with severe preeclampsia. The present review highlights occurrence, diagnosis, complications, surveillance, corticosteroid treatment, mode of delivery and risk of recurrence.

METHODS

Clinical reports and reviews published between 2000 and 2008 were screened using Pub Med and Cochrane databases.

CONCLUSIONS

About 70% of the cases develop before delivery, the majority between the 27th and 37th gestational weeks; the remainder within 48 hours after delivery. The HELLP syndrome may be complete or incomplete. In the Tennessee Classification System diagnostic criteria for HELLP are haemolysis with increased LDH >> 600 U/L), AST >>or= 70 U/L), and platelets < 100 x 10(9)/L. The Mississippi Triple-class HELLP System further classifies the disorder by the nadir platelet counts. The syndrome is a progressive condition and serious complications are frequent. Conservative treatment >>or= 48 hours) is controversial but may be considered in selected cases < 34 weeks' gestation. Delivery is indicated if the HELLP syndrome occurs after the 34th gestational week or the foetal and/or maternal conditions deteriorate. Vaginal delivery is preferable. If the cervix is unfavourable, it is reasonable to induce cervical ripening and then labour. In gestational ages between 24 and 34 weeks most authors prefer a single course of corticosteroid therapy for foetal lung maturation, either 2 doses of 12 mg betamethasone 24 hours apart or 6 mg or dexamethasone 12 hours apart before delivery. Standard corticosteroid treatment is, however, of uncertain clinical value in the maternal HELLP syndrome. High-dose treatment and repeated doses should be avoided for fear of long-term adverse effects on the foetal brain. Before 34 weeks' gestation, delivery should be performed if the maternal condition worsens or signs of intrauterine foetal distress occur. Blood pressure should be kept below 155/105 mmHg. Close surveillance of the mother should be continued for at least 48 hours after delivery.

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) constitute a bone dysplasia family, which is both genetically and phenotypically heterogeneous. The disease spectrum ranges from mild MED, which manifests with pain and stiffness in the joints and delayed and irregular ossification of the epiphyses, to the more severe PSACH, which is characterized by marked short stature, deformity of the legs, and ligamentous laxity. PSACH is almost exclusively caused by mutations in cartilage oligomeric matrix protein (COMP) whereas various forms of MED are caused by mutations in the genes encoding COMP, type IX collagen (COL9A1, COL9A2, and COL9A3), matrilin-3 (MATN3), and solute carrier member 26, member 2 gene (SLC26A2). In this review we discuss specific disease-causing mutations and the clustering of these mutations in functionally and structurally important regions of the respective gene products, genotype to phenotype correlations, and the diagnostic relevance of mutation screening in these osteochondrodysplasias.

BACKGROUND

The previously reported randomised controlled trial of a consensus regimen of pulse cyclophosphamide suggested that it was as effective as a daily oral (DO) cyclophosphamide for remission induction of antineutrophil cytoplasm autoantibodies-associated systemic vasculitis when both were combined with the same glucocorticoid protocol (CYCLOPS study (Randomised trial of daily oral versus pulse Cyclophosphamide as therapy for ANCA-associated Systemic Vasculitis published de groot K, harper L et al Ann Int Med 2009)). The study had limited power to detect a difference in relapse. This study describes the long-term outcomes of patients in the CYCLOPS study.

METHODS

Long-term outcomes were ascertained retrospectively from 148 patients previously recruited to the CYCLOPS Trial. Data on survival, relapse, immunosuppressive treatment, cancer incidence, bone fractures, thromboembolic disease and cardiovascular morbidity were collected from physician records retrospectively. All patients were analysed according to the group to which they were randomised.

RESULTS

Median duration of follow-up was 4.3 years (IQR, 2.95-5.44 years). There was no difference in survival between the two limbs (p=0.92). Fifteen (20.8%) DO and 30 (39.5%) pulse patients had at least one relapse. The risk of relapse was significantly lower in the DO limb than the pulse limb (HR=0.50, 95% CI 0.26 to 0.93; p=0.029). Despite the increased risk of relapse in pulse-treated patients, there was no difference in renal function at study end (p=0.82). There were no differences in adverse events between the treatment limbs.

CONCLUSIONS

Pulse cyclophosphamide is associated with a higher relapse risk than DO cyclophosphamide. However, this is not associated with increased mortality or long-term morbidity. Although the study was retrospective, data was returned in 90% of patients from the original trial.

BACKGROUND

An elevated risk of lung cancer among workers in chromate production facilities has previously been reported. This excess risk is believed to be the result of exposure to hexavalent chromium. There have been mixed reports about whether trivalent chromium exposure is also associated with an excess lung cancer risk. Previous studies of measured hexavalent chromium exposure and lung cancer risk have not examined cigarette smoking as a risk factor.

METHODS

A cohort of 2,357 workers first employed between 1950 and 1974 at a chromate production plant was identified. Vital status of the workers was followed until December 31, 1992. Work histories of cohort members were compiled from the beginning of employment through 1985, the year the plant closed. Annual average exposure estimates, based on historical exposure measurements, were made for each job title in the plant for the years 1950-1985. These exposure estimates were used to calculate the cumulative hexavalent chromium exposure of each member of the study population. Following closure of the plant, settled dust samples were collected and analyzed for hexavalent and trivalent chromium. The trivalent/hexavalent concentration ratios in each plant area were combined with historic air-sampling data to estimate cumulative trivalent chromium exposure for each individual in the study cohort. Smoking status (yes/no) as of the beginning of employment and clinical signs of potential chromium irritation were identified from company records.

RESULTS

Cumulative hexavalent chromium exposure showed a strong dose-response relationship for lung cancer. Clinical signs of irritation, cumulative trivalent chromium exposure, and duration of work were not found to be associated with a risk of lung cancer when included in a proportional hazards model with cumulative hexavalent chromium exposure and smoking. Age-specific data on cumulative hexavalent chromium exposure, observed and expected numbers of lung cancer cases, and person-years of observation are provided.

CONCLUSIONS

Cumulative hexavalent chromium exposure was associated with an increased lung cancer risk; cumulative trivalent chromium exposure was not. The excess risk of lung cancer associated with cumulative hexavalent chromium exposure was not confounded by smoking status. The current study offers the best quantitative evidence to date of the relationship between hexavalent chromium exposure and lung cancer. Am. J. Ind. Med. 38:115-126, 2000. Published 2000 Wiley-Liss, Inc.

BACKGROUND

A high circulating concentration of the amino acid homocysteine is an independent risk factor for stroke. Alzheimer's disease (AD) commonly co-occurs with stroke. Epidemiological studies found associations between hyperhomocysteinaemia and both histologically confirmed AD and disease progression and revealed that dementia in AD was associated with evidence of brain infarcts on autopsy. Thus, hyperhomocysteinaemia and AD could be linked by stroke or microvascular disease. However, given known relations between B-group-vitamin deficiency and both hyperhomocysteinaemia and neurological dysfunction, direct causal mechanisms are also plausible.

BACKGROUND

A recent prospective study (S Seshadri and colleagues N Engl J Med; 2002 346: 476-83) showed hyperhomocysteinaemia to be a strong, independent risk factor for dementia and AD. The researchers found a graded increase in risk of both outcomes with rising plasma concentration of homocysteine after multivariate control for putative risk factors for AD. In conjunction with demonstration of a fall in homocysteine concentrations in response to increasing B-group-vitamin status, these findings give hope that mental decline, or AD itself, could be prevented by dietary modification or food fortification. WHERE NEXT? 25% of dementia cases are attributed to stroke. The possibility that some of the other 75% might be prevented by the lowering of homocysteine concentrations greatly increases the hope of maintaining self-sufficiency into old age. If homocysteine lowering can reduce the incidence of dementia or AD, decreased incidence of these disorders may be seen in Canada and the USA, where government-mandated folate-fortification programmes are in effect. Future research should focus on early detection of AD and on the possibility that the disease itself, or its primary symptom, could be prevented by folate supplementation.

The murine c-myc gene contains two elements responsive to the rel-oncogene-related family of NF-kappa B factors. Previously we have shown that factor binding to these two NF-kappa B elements mediates induction of transcription of the c-myc promoter upon interleukin-1 treatment of human dermal fibroblasts and human T-cell leukemia virus type I tax gene expression in T cells (D. J. Kessler, M. P. Duyao, D. B. Spicer, and G. E. Sonenshein, J. Exp. Med. 176:787-792, 1992; M. P. Duyao, D. J. Kessler, D. B. Spicer, C. Bartholomew, J. L. Cleveland, M. Siekevitz, and G. E. Sonenshein, J. Biol. Chem. 267:16288-16291, 1992). To begin to delineate the specific roles of the individual members of the NF-kappa B family, here we have tested their effects on activation of a c-myc promoter/exon 1-CAT construct in NIH 3T3 cells. Classical NF-kappa B (p65/p50) was a potent transcriptional activator of the c-myc promoter. Cotransfection with either p65 alone or p65 in combination with p50 mediated significant induction. In contrast, expression of either v-rel or chicken c-rel failed to transactivate, while murine c-rel induced c-myc promoter activity only slightly. Furthermore, induction by classical NF-kappa B was inhibited by coexpression of either v-rel or chicken c-rel. Thus, individual members of the rel family have differential effects of the c-myc promoter, which can modulate overall transcriptional activity and allow for precise regulation of this oncogene under diverse physiologic conditions.

Immunocompetent adult mice mount a vigorous cytotoxic T lymphocyte (CTL) response against the Armstrong (ARM) 53b strain of LCMV after primary inoculation. In contrast, the Clone 13 variant of ARM 53b, originally isolated from the spleen of a persistently infected mouse, suppresses LCMV-specific CTL responses (R. Ahmed et al. (1984) J. Exp Med 60, 521). The induction and generation of CTL maps to the short (S) RNA segment and not the long (L) RNA segment of LCMV (Y. Riviere et al. (1986) J. Immunol. 136, 304). The CTL recognition epitope, expressed in virus-infected target cells, also maps to the S segment of the LCMV ARM genome, and is structurally and functionally intact in Clone 13-infected target cells. Here we report the S RNA sequences of both ARM 53b and its variant Clone 13. Comparison reveals a single amino acid difference. However, sequence divergence at this position also occurs among other strains of LCMV (Pasteur, Traub, WE) which do elicit CTL responses. Hence, (1) the amino acid difference is unrelated to the phenotypic divergence of Clone 13, (2) suppression of the CTL response by Clone 13 is not linked to the CTL recognition epitope, and (3) the structure or function responsible for CTL immunosuppression by Clone 13 most likely maps to the L RNA segment. Further, the availability of the complete S RNA sequence for LCMV ARM and ARM Clone 13 variant allows a detailed comparison with WE (V. Romanowski et al. (1985) Virus Res. 3, 110-114), the only other LCMV S RNA so far sequenced.