Autoantibodies as biomarkers for the prediction of neuropsychiatric events in systemic lupus erythematosus.

OBJECTIVE: Neuropsychiatric events occur unpredictably in systemic lupus erythematosus (SLE) and most biomarker associations remain to be prospectively validated. This study examined a disease inception cohort of 1047 SLE patients to determine which autoantibodies at enrolment predicted subsequent neuropsychiatric events. METHODS: Patients with a recent SLE diagnosis were assessed prospectively for up to 10 years for neuropsychiatric events using the American College of Rheumatology case definitions. Decision rules of graded stringency determined whether neuropsychiatric events were attributable to SLE. Associations between the first neuropsychiatric event and baseline autoantibodies (lupus anticoagulant (LA), anticardiolipin, anti-ß(2) glycoprotein-I, anti-ribosomal P and anti-NR2 glutamate receptor) were tested by Cox proportional hazards regression. RESULTS: Disease duration at enrolment was 5.4 ± 4.2 months, follow-up was 3.6 ± 2.6 years. Patients were 89.1% female with mean (±SD) age 35.2 ± 13.7 years. 495/1047 (47.3%) developed one or more neuropsychiatric event (total 917 events). Neuropsychiatric events attributed to SLE were 15.4% (model A) and 28.2% (model B). At enrolment 21.9% of patients had LA, 13.4% anticardiolipin, 15.1% anti-ß(2) glycoprotein-I, 9.2% anti-ribosomal P and 13.7% anti-NR2 antibodies. LA at baseline was associated with subsequent intracranial thrombosis (total n=22) attributed to SLE (model B) (HR 2.54, 95% CI 1.08 to 5.94). Anti-ribosomal P antibody was associated with subsequent psychosis (total n=14) attributed to SLE (model B) (HR 3.92, 95% CI 1.23 to 12.5, p=0.02). Other autoantibodies did not predict neuropsychiatric events. CONCLUSION: In a prospective study of 1047 recently diagnosed SLE patients, LA and anti-ribosomal P antibodies are associated with an increased future risk of intracranial thrombosis and lupus psychosis, respectively.

Downregulation of cell surface CA125/MUC16 induces epithelial-to-mesenchymal transition and restores EGFR signalling in NIH:OVCAR3 ovarian carcinoma cells.

BACKGROUND: Epithelial ovarian cancer (EOC) cells are prone to metastasise throughout the peritoneal cavity. The epithelial-to-mesenchymal transition (EMT) is a necessary step towards metastatic tumour progression. CA125/MUC16 mucin is a high-molecular-weight glycoprotein overexpressed in the majority of serous carcinomas, suggesting a possible role in the pathogenesis of these cancers. METHODS: The role of CA125/MUC16 in EMT was investigated using single-chain antibody-mediated knockdown of cell surface CA125/MUC16 in overexpressing EOC NIH:OVCAR3 cells. RESULTS: CA125/MUC16 knockdown was associated with morphological alterations along with decreased surface expression of epithelial markers (E-cadherin, cytokeratin-18) and increased expression of mesenchymal markers (N-cadherin, vimentin). Co-immunoprecipitation experiments revealed that CA125/MUC16 binds to E-cadherin and ß-catenin complexes. The in vitro studies showed disruption of cell-cell junctions, enhanced motility, migration and invasiveness in CA125/MUC16 knockdown cells. Enhanced epidermal growth factor receptor (EGFR) activation was observed in CA125/MUC16 knockdown cells along with increased Akt and ERK1/2 phosphorylation, which are downstream effectors of EGFR, and increased MMP-2 and MMP-9 expression and activities. Epidermal growth factor receptor inhibition strongly inhibited the motility of CA125/MUC16 knockdown cells. CONCLUSIONS: Our findings suggest that CA125/MUC16 plays a role in EMT, presumably through its interaction with E-cadherin and ß-catenin complexes and by modulating EGFR and its downstream signalling pathway in NIH:OVCAR3 cells.

The complete genome of the crenarchaeon Sulfolobus solfataricus P2.

The genome of the crenarchaeon Sulfolobus solfataricus P2 contains 2,992,245 bp on a single chromosome and encodes 2,977 proteins and many RNAs. One-third of the encoded proteins have no detectable homologs in other sequenced genomes. Moreover, 40% appear to be archaeal-specific, and only 12% and 2.3% are shared exclusively with bacteria and eukarya, respectively. The genome shows a high level of plasticity with 200 diverse insertion sequence elements, many putative nonautonomous mobile elements, and evidence of integrase-mediated insertion events. There are also long clusters of regularly spaced tandem repeats. Different transfer systems are used for the uptake of inorganic and organic solutes, and a wealth of intracellular and extracellular proteases, sugar, and sulfur metabolizing enzymes are encoded, as well as enzymes of the central metabolic pathways and motility proteins. The major metabolic electron carrier is not NADH as in bacteria and eukarya but probably ferredoxin. The essential components required for DNA replication, DNA repair and recombination, the cell cycle, transcriptional initiation and translation, but not DNA folding, show a strong eukaryal character with many archaeal-specific features. The results illustrate major differences between crenarchaea and euryarchaea, especially for their DNA replication mechanism and cell cycle processes and their translational apparatus.

PCR analysis of immunoglobulin heavy chain (IgH) and TcR-gamma chain gene rearrangements in the diagnosis of lymphoproliferative disorders: results of a study of 525 cases.

This report summarizes a cumulative 4-year experience in polymerase chain reaction (PCR) analysis of immunoglobin heavy chain (IgH) and TcR-gamma chain gene rearrangements in 525 cases of lymphoproliferative disorders. Because the sensitivity of the PCR methodology was found to be tissue dependent, in the study of the presence of clonal cell population in tissues containing a small number of polyclonal lymphocytes, such as skin and gastrointestinal biopsy specimens, we used the multiple-PCR run approach. In this latter methodology, we repeat the PCR reaction from the same sample at least three times to confirm the reproducibility of the results. In the study of 273 cases of B- or T-cell lymphomas with characteristic immunomorphological and clinical features, a clonal IgH or TcR-gamma chain gene rearrangement was detected in approximately 80% of cases. A clonal rearrangement involving both IgH and TcR-gamma chain genes was found in 10% of cases of both B-cell and T-cell lymphomas. The study of 167 cases of nonneoplastic lymphoid tissue samples showed the presence of clonally rearranged cell populations for IgH or TcR-gamma genes in 3 and 9% of cases, respectively. We also applied PCR for the study of 85 cases of lymphoproliferations with no definite diagnosis (i.e., benign versus malignant) after immunomorphological analysis. In 65 cases (76%), the correlation of immunomorphological features with the presence (48 cases) or the absence (17 cases) of clonal lymphoid cell populations led to a definite diagnosis. In almost all these cases, the final diagnosis was found to be in agreement with the clinical course. In the 20 remaining cases (24%), no definite diagnosis could be made. We also assessed the value of PCR in detecting bcl-2/J(H) gene rearrangement as an additional clonal marker in the diagnosis of follicular lymphoma. Bcl-2/J(H) rearrangement and/or IgH gene rearrangement was found in approximately 85% (71/85) of follicular lymphoma cases studied.

Kaposi's sarcoma-associated herpesvirus (KSHV) in bone marrow biopsies of patients with Waldenstrom's macroglobulinaemia.

Kaposi's sarcoma-associated herpesvirus (KSHV) is suspected to play a role in the aetiology of multiple myeloma. Because of similarities in the pathophysiology of multiple myeloma and Waldenstrom's macroglobulinaemia (WM), we investigated DNA samples from 20 bone marrow biopsies with WM for the detection of KSHV by PCR (KS330/ORF26). We performed two rounds of amplification and found that only 1/20 of the DNA samples obtained from biopsies had a detectable KSHV sequence. The positive patient was also infected by the human immunodeficiency virus (HIV). Our data provide evidence that KSHV cannot be implicated in the pathogenesis of WM.

The evaluation of Franco-Quebec victims of child sexual abuse and their mothers: the implementation of a standard assessment protocol.

OBJECTIVE: There were two aims: first, to evaluate the feasibility of applying a standard assessment protocol to Franco-Quebec victims of child sexual abuse and nonoffending mothers; and second, to compare results from an initial sample with available data from English-speaking samples. METHOD: A standard individual case study design was used for victims and mothers; and the satisfaction of the nine participating youth workers was assessed. Four self-report instruments for victims and five for mothers were chosen on the bases of workers' priorities, sensitivity to the impact of CSA, and the availability of published norms on English-speaking samples. Results are reported on 48 confirmed victims and 40 nonoffending mothers. RESULTS: The protocol was favorably received by the CPS workers, supervisors and all mothers and victims. Percentages of clinically distressed victims varied from highs of 68% on the externalization difficulties of the Child Behavior Checklist and 67% for 2- to 6-year-olds on the Child Sexual Behavior Inventory, to lows of 10% on hostility symptoms and 13% on the Dissociation Scale of the Trauma Symptom Check for Children. The rate of symptom-free children was lower (19%) and that of revictimization higher (30%) than most published estimates (Kendall-Tackett, Williams, & Finkelhor, 1993). Most mothers reported elevated emotional distress (depression, 59%) and symptoms of post-traumatic stress (intrusiveness, 67%). Although 87% of mothers believed the allegations, only 45% offered adequate emotional support. CONCLUSION: The implementation phase of this research was successful, given the positive reactions of workers and clients. Results on standard instruments from this French-speaking sample were similar to profiles of English-speaking victims and their mothers but firm conclusions on appropriate norms will require larger samples, cross cultural contrasts, and the evaluation of additional variables.

Assessment of the efficacy of iodine-131 for thyroid ablation.

It is customary to ablate residual tissue after near-total thyroidectomy for thyroid carcinoma by administering 131I. A recent trend has been to use lower 131I doses. This study was designed to assess the efficacy of thyroid ablation by 1110 MBq of 131I (30 mCi) in patients who had near-total thyroidectomy for papillary, mixed or follicular thyroid carcinoma. Four months after surgery, a whole-body scan was done using 185 MBq (5 mCi) of 131I after withdrawal of L-thyroxine for 5-6 wk. Residual thyroid area was then measured by planimetry of the thyroid scan. Patients received ablation therapy within 5 days after scanning and one or more subsequent scans were performed 6 mo later. Forty-four patients were treated to ablate residual functional thyroid tissue. Of these, 12 (27%) had successful ablation. Total body areas (1.63 +/- 0.16 versus 1.83 +/- 0.30, p < 0.03) and residual thyroid tissue (1.4 +/- 1.4 versus 2.0 +/- 1.2 cm2, p < 0.05) were less in patients with total thyroid ablation while there was a trend for a smaller incidence of associated goiter in those patients (1/12 versus 13/32, p < 0.07). Nine of the 17 (53%) patients with a total body area less than 1.9 m2 and/or with a residual thyroid tissue less than 2.1 cm2 and/or without associated previous associated diffuse or multinodular goiter had a total thyroid ablation, while 3 of the 27 (11%) patients who did not have these characteristics had a successful therapy (p < 0.005). Our data suggest that 1110 MBq (30 mCi) of 131I can achieve total ablation of residual thyroid tissue after near-total thyroidectomy particularly in patients with lower total body area and smaller residual thyroid tissue without associated previous diffuse or multinodular goiter.

Relationships between acetone, cataracts, and ascorbate in hairless guinea pigs.

Acetone is one of the most commonly used industrial solvents. Recent literature indicated that in guinea pigs, but not rabbits, acetone is cataractogenic and that elevated acetone exposure is also associated with depressed aqueous ascorbate levels. Other work indicated that aqueous and lens levels of ascorbate are closely linked and that depressed ascorbate status is related to cataract. Taken together, these papers suggested that acetone exposure, depressed ascorbate levels, and cataract are related, possibly causally. While the possibility that acetone is cataractogenic presented a major health concern, it also presented an opportunity to develop a new model of cataract in which hypotheses regarding anticataractogenic effects of ascorbate could be tested. Albino hairless guinea pigs are immunocompetent animals derived from albino Hartley guinea pigs. Animals were fed diets containing low (4.9 mg/day) and high (55 mg/day) levels of ascorbate. This resulted in distinct groups of animals, one with high tissue ascorbate levels and the other with low, but nonscorbutic ascorbate levels. The tissue levels of ascorbate and the relationship between tissue ascorbate levels and dietary intake indicate that with respect to ascorbate uptake, transport, and concentration, these animals are identical to the standard albino Hartley animals. Daily exposure to acetone was extended for 6 months, with a total applied dose of 65 ml. Absorption of the solvent was maximized by the use of hairless animals. Despite exposure of the animals to higher levels of acetone, in no case (n = 20) were cataracts observed over a 2-year period. This is consistent with results using rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgen receptor-mediated stimulation of 17 beta-hydroxysteroid dehydrogenase activity by dihydrotestosterone and medroxyprogesterone acetate in ZR-75-1 human breast cancer cells.

The estrogen-sensitive human breast cancer cell line ZR-75-1 was used to study the regulation of 17 beta-hydroxysteroid dehydrogenase (17 beta HSD), the enzyme responsible for the interconversion of estrone (E1) and estradiol (E2). We, thus, investigated the effects of a 6-day exposure to various steroids or growth factors on the reductive (E1-->E2) and oxidative (E2-->E1) 17 beta HSD activities in ZR-75-1 cells as measured during a subsequent 16-h incubation with [3H]E1 or [3H]E2. The reductive 17 beta HSD activity was approximately 3-fold higher than the corresponding oxidative (E2-->E1) activity in control cells, thus favoring the predominance of E2 within the cell. Exposure to dihydrotestosterone (DHT) increased by 1.4-fold the reductive 17 beta HSD activity, with the stimulatory effect exerted at an EC50 value of 0.09 nM DHT, while the oxidative pathway was increased by 4.15-fold at an EC50 value of 0.17 nM. Incubation with medroxyprogesterone acetate, on the other hand, enhanced reductive 17 beta HSD activity by 1.87-fold, while the same treatment increased oxidative 17 beta HSD activity by 2.85-fold; the effects were exerted at EC50 values of 0.4 and 5 nM, respectively. The stimulatory effect of both steroids on 17 beta HSD activity was almost completely reversed by simultaneous exposure to the pure antiandrogen hydroxyflutamide (3 microM), thus supporting an action exerted through the androgen receptor. On the other hand, the synthetic estrogen ethynyl estradiol (EE2) inhibited the reductive and oxidative 17 beta HSD activities by 40% and 33%, respectively, whereas dexamethasone (300 nM) increased by 2.5- and 1.9-fold the reductive and oxidative 17 beta HSD activities, respectively. The present data showing that DHT and the androgenic compound medroxyprogesterone acetate favor the degradation of E2 into E1 suggest that the potent antiproliferative activity of these two compounds in E2-stimulated ZR-75-1 human breast cancer cells could be at least partially exerted through changes in 17 beta HSD activity.

[Radiotherapy or the preservation of the organ and its function]. / La radiothérapie ou la préservation de l'organe et de la fonction.

Radiation therapy is increasingly used as a cancer treatment to avoid mutilating surgery. We first review the cancer sites where this role was first established (head and neck cancer, breast and prostate cancers). Then we examine the cancer sites where radiation treatments have only recently replaced amputation or other mutilating surgery (soft tissue sarcomas, anal and oesophageal cancers). Finally we review some sites where research in organ preservation is still ongoing, for example eye tumors and bladder cancer.

Androgens and breast cancer.

We have recently demonstrated that physiological levels of androgens exert direct and potent inhibitory effects on the growth of human breast cancer ZR-75-1 cells in vivo in nude mice as well as in vitro under both basal and estrogen-stimulated conditions. The inhibitory effect of androgens has also been confirmed on the growth of dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in the rat. Such observations are in close agreement with the clinical data showing that androgens and the androgenic compound medroxyprogesterone acetate (MPA) have beneficial effects in breast cancer in women comparable to other endocrine therapies, including tamoxifen. Although the inhibitory action of androgens on cell proliferation in estrogen-induced ZR-75-1 cells results, in part, from their suppressive effect on expression of the estrogen receptor, the androgens also exert a direct inhibitory effect independent of estrogens. Androgens cause a global slowing effect on the duration of the cell cycle. These observations support clinical data showing that androgenic compounds induce an objective remission after failure of antiestrogen therapy as well as those indicating that the antiproliferative action of androgens is additive to that of antiestrogens. We have also recently demonstrated in ZR-75-1 human breast cancer cells the antagonism between androgens and estrogens on the expression of GCDFP-15 and GCDFP-24 which are two major proteins secreted in human gross cystic disease fluid. The effects of androgens and estrogens as well as those of progestins and glucocorticoids on GCDFP-15 and GCDFP-24 mRNA levels and secretion are opposite to those induced by the same steroids on cell growth in ZR-75-1 cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Multiple steroid metabolic pathways in ZR-75-1 human breast cancer cells.

In order to characterize the main enzymatic systems involved in androgen and estrogen formation as well as metabolism in ZR-75-1 human breast cancer cells, incubation of intact cells was performed for 12 or 24 h at 37 degrees C with tritiated estradiol (E2), estrone (E1), androst-5-ene-3 beta, 17 beta-diol (5-ene-diol), dehydroepiandrosterone (DHEA), testosterone (T), androstenedione (4-ene-dione), dihydrotestosterone (DHT) or androsterone (ADT). The extra- and intracellular steroids were extracted, separated into free steroids, sulfates and non-polar derivatives (FAE) and identified by HPLC coupled to a Berthold radioactivity monitor. Following incubation with E2, 5-ene-diol or T, E1, DHEA and 4-ene-dione were the main products, respectively, thus indicating high levels of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD). When 4-ene-dione was used, on the other hand, a high level of transformation into 5 alpha-androstane-3,17-dione (A-dione), Epi-ADT and ADT was found, thus indicating the presence of high levels of 5 alpha-reductase as well as 3 alpha- and 3 beta-hydroxysteroid dehydrogenase. Moreover, some T was formed, due to oxidation by 17 beta-HSD. No estrogen was detected with the androgen precursors T or 4-ene-dione, thus indicating the absence of significant aromatase activity. Moreover, significant amounts of sulfates and non-polar derivatives were found with all the above-mentioned substrates. The present study shows that ZR-75-1 human breast cancer cells possess most of the enzymatic systems involved in androgen and estrogen formation and metabolism, thus offering an excellent model for studies of the control of sex steroid formation and action in breast cancer tissue.

Wide spectrum of steroids serving as substrates for the formation of lipoidal derivatives in ZR-75-1 human breast cancer cells.

Recently, several natural steroids have been found to be esterified to long-chain fatty acids (FAE) in various mammalian tissues. The purpose of the present study was to determine the ability of a series of 3H-labeled steroids to serve as substrates for the formation and accumulation of such non-polar derivatives in intact cells, using the hormone-responsive ZR-75-1 human breast cancer cell line as model. All 14 steroids tested were found to be converted, directly or following further metabolism, to lipoidal ester derivatives. The percentage of intracellular steroids recovered as FAE derivatives was usually substantial (14-90%), especially in the case of C-19 steroids (75-90%). The composition of the lipoidal steroid fractions recovered from the labeled cell extracts was characterized by chromatographic comparison with synthetic steroid FAEs and by saponification of the steroid FAEs and identification of the released steroidal moieties. Following metabolism, most steroid substrates were converted into multiple lipoidal esters. Furthermore, 5 alpha-androstane-3 alpha, 17 beta-diol, 5 alpha-androstane-3 beta, 17 beta-diol, as well as androst-5-ene-3 beta, 17 beta-diol formed lipoidal diesters in addition to the monoester form. The high level of intracellular steroid FAE accumulation reported in this study suggests that these yet poorly known steroid derivatives may play important functions in the regulation of steroid hormone metabolism and action.

Extensive esterification of adrenal C19-delta 5-sex steroids to long-chain fatty acids in the ZR-75-1 human breast cancer cell line.

Estrogen-sensitive human breast cancer cells (ZR-75-1) were incubated with the 3H-labeled adrenal C19-delta 5-steroids dehydroepiandrosterone (DHEA) and its fully estrogenic derivative, androst-5-ene-3 beta,17 beta-diol (delta 5-diol) for various time intervals. When fractionated by solvent partition, Sephadex LH-20 column chromatography and silica gel TLC, the labeled cell components were largely present (40-75%) in three highly nonpolar, lipoidal fractions. Mild alkaline hydrolysis of these lipoidal derivatives yielded either free 3H-labeled DHEA or delta 5-diol. The three lipoidal fractions cochromatographed with the synthetic DHEA 3 beta-esters, delta 5-diol 3 beta (or 17 beta)-monoesters and delta 5-diol 3 beta,17 beta-diesters of long-chain fatty acids. DHEA and delta 5-diol were mainly esterified to saturated and mono-unsaturated fatty acids. For delta 5-diol, the preferred site of esterification of the fatty acids is the 3 beta-position while some esterification also takes place at the 17 beta-position. Time course studies show that ZR-75-1 cells accumulate delta 5-diol mostly (greater than 95%) as fatty acid mono- and diesters while DHEA is converted to delta 5-diol essentially as the esterified form. Furthermore, while free C19-delta 5-steroids rapidly diffuse out of the cells after removal of the precursor [3H]delta 5-diol, the fatty acid ester derivatives are progressively hydrolyzed, and DHEA and delta 5-diol thus formed are then sulfurylated prior to their release into the culture medium. The latter process however is rate-limited, since new steady-state levels of free steroids and fatty acid esters are rapidly reached and maintained for extended periods of time after removal of precursor, thus maintaining minimal concentrations of intracellular steroids. The rapid rate and large extent of esterification of DHEA and delta 5-diol to long-chain fatty acids in breast cancer cells indicate that this reaction could constitute an important regulatory step in the estrogenic action of DHEA and delta 5-diol in these cells.

Malignant parotid tumors. Prognostic factors and optimum treatment.

A retrospective study of 271 patients with parotid carcinoma seen between 1958 and 1980 is reported. Among these were 64 (24%) mucoepidermoid tumors (all degrees of differentiation), 50 (18%) adenocarcinomas, 40 (15%) malignant mixed tumors, 39 (14%) adenoid cystic carcinomas, 37 (14%) undifferentiated, 21 (8%) acinic, and 20 (7%) squamous cell carcinomas. The proportion of advanced (T3T4) to early (T1T2) tumors was 1.7:1. At diagnosis, 42 (15%) patients had regional metastases. An analysis for prognostic factors showed that the histology, tumor stage, regional metastases (No vs. N+), age, and damage to the facial nerve all influence cause-specific survival. After multivariate analysis the tumor size and the presence of regional metastases were the two most significant factors (p less than 0.0001 and 0.004). The prognostic characteristics were similar for the 67 (25%) patients treated by surgery and for the 169 (62%) patients treated with surgery and postoperative radiotherapy. Patients treated with combined therapy had a 10-year relapse-free rate of 62% compared to 22% for those treated by surgery alone (p = 0.0005).

Malignant salivary gland tumors.

A retrospective review of 403 patients with salivary gland tumors seen between 1958 and 1980 and a mean follow-up of 10 years is reported. The median age was 58 (7-94) years and the male to female ratio 1.3:1. There were 293 (72%) parotid, 83 (21%) submaxillary and 27 (7%) tumors developed at other sites. Among these were 84 (22%) mucoepidermoid (all degrees of differentiation), 87 (22%) adenocystic carcinomas, 70 (17%) adenocarcinomas, 25 (6%) acinic, 26 (6%) squamous cell, 44 (11%) undifferentiated, 52 (13%) mixed and 12 (3%) nonspecified carcinomas. A painless lump was the first symptom in 338 (84%) patients. The first planned treatment was surgery in 110 (27%), radiotherapy in 50 (12%), and surgery and radiotherapy combined in 239 (59%) patients. Following the first treatment, the primary parotid tumor was controlled by surgery in 17/70 (24%), by irradiation in 6/39 (15%) and surgery and radiation combined in 134/182 (74%) patients. Altogether, regional metastases developed in 36 (12%) and distant metastases in 36 (12%) of 293 patients with parotid tumors. For the submandibular tumors the primary tumor was controlled by surgery in 9/31 (29%), 0/4 (0%) by irradiation, and in 32/46 (70%) by surgery and irradiation. Here, regional and distant metastases developed in 16/84 (19%) and 19/84 (23%) patients. Among the other sites the primary tumor was controlled by surgery in 4/9 (44%), 0/7 (0%) by irradiation, and in 8/11 (73%) by surgery and radiotherapy combined. In this group 4/27 (15%) and 5/27 (18%) patients developed regional and distant metastases. The 5- and 10-year cause specific survival rates were 65 and 59% for the parotid tumors, 61 and 48% for the submaxillary tumors and 62 and 52% for the other sites. These results clearly demonstrate the advantages of combining surgery and radiotherapy as the first planned treatment for most tumors.

Globin chain synthesis in Hb J Baltimore-beta (+)-thalassemia.

An American black family in whom hemoglobin J Baltimore and beta (+)-thalassemia genes coexisted is described. The proposita is a 23-year-old woman with a hemoglobin (Hb) level of 11.5 g/dl, microcytic, hypochromic indices, increased values of Hbs A2 and F, and alpha/non-alpha synthetic ratio of 1.52. Hbs A and J Baltimore (beta 16 Gly---Asp) constituted 12% and 81.3%, respectively, of her total hemoglobin. Her sister had a very similar peripheral blood picture, but Hbs A and J Baltimore constituted 6.8% and 85.5%, respectively, of her total hemoglobin, and the alpha/non-alpha synthetic ratio was 1.39. The mother had beta(+)-thalassemia trait only, a moderate degree of anemia, and greater synthetic imbalance (alpha/non-alpha raio of 1.73). These findings suggest that the presence of the Hb J Baltimore gene ameliorates the effects of a coexistent beta-thalassemia gene.