Untreated chronic lymphocytic leukemia concurrent with or followed by acute myelogenous leukemia or myelodysplastic syndrome. A report of five cases and review of the literature

Although it has been known that patients with chronic lymphocytic leukemia (CLL) have a higher frequency of second malignant neoplasms, the development of acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) in these patients is extremely rare. Most reported cases have been therapy-related. In this article, we report the clinical and immunophenotypic features of 5 cases of untreated CLL concurrent with or followed by the development of AML or MDS. All 5 patients were men, with ages ranging from 57 to 87 years (mean, 73.8 years). Four patients had AML and 1 patient had refractory anemia with ringed sideroblasts. In the 4 cases of AML and CLL, 2 distinct cell populations (i.e., myeloblasts and lymphocytes) were identified morphologically and/or immunophenotypically. Our findings support that this rare concurrence of AML or MDS and untreated CLL may represent 2 separate disease processes.     

QT dispersion in the surface electrocardiogram in elderly patients with major depression

Background: QT dispersion (QTd) is a measure of interlead variations of QT interval of the surface 12-lead electrocardiogram (ECG). Increased QTd, found in various cardiac diseases, reflects cardiac instability and is associated with increased cardiac death. Major depressive disorder (MDD) was found to be associated with high cardiovascular mortality rates. This study compares QTd in elderly patients with MDD to normal controls. Methods: QTd and rate-corrected QTd of 18 physically healthy elderly patients (69.9±7.6 years) with MDD was compared to nine physically and mentally healthy age- and gender-matched controls (64.1±12.2 years). Results: QTd and rate-corrected QTd were significantly higher in MDD compared to controls (68±30 vs. 40±13 ms, P=0.002 and 81±39 vs. 43±13 ms, P=0.001, respectively). Intra- and inter- observer reproducibilities were highly correlated (r=0.96, P <0.0001; r=0.88, P <0.001, respectively). Limitations and Conclusions: The major limitations of this study are the small number of subjects and the fact that all the patients were maintained on antidepressant medication. However, it seems that QTd analysis might shed light on possible autonomic imbalance and also provide a novel cardiovascular risk factor for increased cardiac death in MDD.     

Bone turnover and its relationship with bone mineral density in pre- and postmenopausal women with or without fractures

Objective: This work was carried out in order to investigate possible relationships between bone turnover rate, as evaluated by bone biomarkers and skeletal mass, as evaluated by bone mineral density (BMD). Method: Fifty-eight normal women and 30 female patients with osteoporotic fractures were enrolled. Three groups were defined: (1) fertile subjects (n=24), mean age 33.7±8.1 years; (2) postmenopausal women (n=32, including 11 patients with fractures) whose BMD values, in terms of T score, were less than −2.5 S.D. below the young adult mean obtained in our laboratory (mean age 61.7±7.9 years; and years since menopause (ysm), 12.6±8.3); (3) postmenopausal women (n=32, including 19 patients with fractures) whose BMD values in terms of T score, were below −2.5 S.D. (mean age 62.9±8.6 years; and ysm 15.9±9.0). Groups II and III characterised, by inclusion criteria, by significant different mean BMD values, were similar as far as chronological and menopausal age were considered. Metabolic tests included a short urine collection to determine calcium, hydroxyproline, cross-linked N-telopeptides of type I collagen (NTx) and creatinine (Cr); half-way through this collection, a blood sample was taken for the measurement of total alkaline phosphatase activity (ALP) and tartrate-resistant acid phosphatase activity (TRAP). BMD at lumbar spine was evaluated. Results: There were significant differences amongst the three groups in mean ALP (P<0.001, by analysis of variance) TRAP (P<0.006) and NTx/Cr (P<0.001) values, but not as far as mean values of calcium/Cr or hydroxyproline/Cr ratios were concerned. Considering the group as a whole, there were significant inverse correlations between NTx/Cr, ALP, TRAP and BMD controlling for both age (r=−0.392, P<0.001; r=−0.447, P<0.001 and r=−0.327, P<0.002, respectively) and ysm (r=−0.374, P<0.001; r=−0.474, P<0.001 and r=−0.333, P<0.002). Conclusions: Our results indicate, that, even after controlling for both ageing and oestrogen status, there is an inverse relationship between bone mass (that at a given time represents the balance of all previous metabolic events) and a biochemical marker (which reflects bone turnover at the time of examination). These findings are in line with the belief that increased bone turnover should be regarded as a risk factor for osteoporosis. Furthermore, our results indicate that, unless there is no increase of hepatic isozyme, total ALP still maintains a possible role as a first analysis to evaluate bone turnover before requesting markers with greater specificity, sensitivity but also more expensive and whose analysis is sometimes time-consuming.     

Worsening of depressive symptoms 6 months after an acute coronary event in older adults is associated with impairment of cardiac autonomic function

Background: Depression increases mortality of coronary patients, and autonomic dysfunction has been proposed as an explanation for this association. Methods: In a sample of 38 adults ≥ 60 years with myocardial infarction or unstable angina, we studied depression (presence of a major depressive episode and 21-item Hamilton depression score) and heart rate variability (HRV) of 550 normal beats shortly after admission to the coronary care unit (CCU). Thirty patients were alive at 6 months and were studied at that time as well. Spectral HRV measurements included power in the high-frequency range (HF, 0.15—0.55 Hz, a measure of parasympathetic activity) and low-frequency range (LF, 0.03—0.15 Hz). Nonspectral HRV measurements included standard deviation of normal beats (SDNN) and two measures of vagal activity: percentage of adjacent cycles differing by >50 ms (pNN50) and the root-mean-square of differences in successive beats (rMSNN). Results: Patients who died within 6 months (n=8) had a higher Hamilton-D score than survivors (13.9±6.5 vs. 18.4±5.6, P=0.039) and were more likely to have an episode of major depression upon admission to the CCU (71 vs. 27%, P=0.027). An increase in Hamilton-D score at 6 months correlated with a decrease in total (r=–0.48, P=0.014), high-frequency (r=–0.49, P=0.007), and low-frequency HRV (r=–0.46, P=0.014). Limitations: Patients belonged to a single institution and there was a small proportion of men. Conclusions: Progression of mood symptoms 6 months after an acute coronary event is associated with an impairment of autonomic control of the heart in elderly individuals.     

Effects of postmenopausal hypoestrogenism on skin collagen

Objective: The aim of our study was to evaluate the effect of aging and postmenopausal hypoestrogenism on skin collagen content. Methods: Thirty-two women (mean age 48.78±9.86; year±S.D., range 28–68), 14 in premenopause and 18 in postmenopause, underwent skin biopsies performed during laparotomic operation. The amount of collagen type I, III and type III/type I ratio was evaluated by immunohistochemistry and computerised image analysis, and was related to age and years of postmenopause. Results: In the postmenopausal patients, a significant (P<0.01) decrease of percentage of skin collagen type I, type III and type III/type I ratio was observed in comparison to premenopausal women. The percentages of collagen type I, type III and type III/I ratio of all patients studied was significantly (P<0.01) correlated with chronological age (r=0.88, 0.89 and 0.61, respectively). Considering only postmenopausal subjects, the correlation with chronological age was significant (P<0.01) for collagen type I and type III of postmenopausal women (r=0.59, r=0.64, respectively), but not for the type III/I ratio (r=0.37, P=0.131). The percentages of collagen type I, type III and type III/I ratio of postmenopausal women showed a significant (P<0.01) inverse correlation with years of postmenopause (r=0.76, 0.73 and 0.73, respectively). Conclusions: Our data suggest that the decrease of skin collagen is an estrogen-related phenomenon.     

Hormone replacement therapy improves arterial stiffness in normotensive postmenopausal women

Objectives: Aortic stiffness, determined by the pulse wave velocity (PWV), is an independent marker of cardiovascular risk. PWV is mainly influenced by age-associated alterations of arterial wall structure and blood pressure (BP). To determine the impact of hormone replacement therapy (HRT) on arterial compliance in normotensive, postmenopausal women, we examined the effects of HRT on PWV. Methods: Fifty-six postmenopausal women aged 50–70 years were recruited into the present retrospective study from the patients visiting our menopause clinic. Twenty-seven women who were prescribed HRT (14 on estrogen alone and 13 on estrogen plus progestogen) for several months to 6 years and an age-matched group of 29 women not on HRT were studied (Study 1). Nine postmenopausal women were also studied before and at 4 weeks of the treatment of estrogen replacement therapy (ERT) (Study 2). Brachial to ankle PWV (baPWV), which is correlated with aortic PWV, was determined using an automatic device, BP-203PRE. Results: In Study 1, PWV was significantly correlated with age in both groups (controls: r=0.392, P=0.035; HRT group: r=0.471, P=0.013), and HRT significantly lowered the PWV value at all ages examined (Mean±S.D. of baPWV in controls: 1382.2±114.1; HRT: 1245.3±124.8, P=0.0001). In Study 2, baPWV decreased significantly after ERT (P<0.05), without a significant change in systolic BP (P=0.851). Conclusions: Estrogen appears to improve arterial compliance independently of BP within 4 weeks.     

Down-Regulation of CD25 Expression on the Surface of Activated Tumor-Infiltrating Lymphocytes in Human Cervical Carcinoma

ABSTRACT: To investigate the activation status of tumor-infiltrating lymphocytes (TILs) within the tumor milieu of human cervical carcinoma, we quantitatively measured and compared the activation markers on lymphocyte subpopulations which infiltrating normal and neoplastic cervix. A total of 20 patients with stage IA to IIA cervical cancer (cancer group) and 10 women with normal cervix (control group) were enrolled in this study. Mononuclear cells were isolated from tissue specimens by mechanical dispersal technique and three-color flow cytometry was utilized for the quantification of activation markers on lymphocyte subsets. Compared with control group, lymphocytes isolated from cancer tissue consisted of higher proportions of B cells (7.23% ± 4.49% vs. 3.67% ± 3.19%, P = 0.016) and T cells (72.33% ± 8.70% vs. 53.15% ± 17.36%, P = 0.004), but an inverted CD4:CD8 ratio (0.74 ± 0.27 vs. 1.14 ± 0.28, P = 0.002) and decreased NK cells (7.53% ± 4.33% vs. 16.00% ± 11.82%, P = 0.035). Low expression of CD25, but not CD69 and HLA-DR was observed on both CD4⁺CD3⁺ and CD8⁺CD3⁺ T cells derived from cervical cancer (P < 0.0001). Further dual activation marker analysis demonstrated that the expression of CD25 was dissociated from CD69 and HLA-DR on the same TILs in cancer tissue (P < 0.001). TILs in the tumor microenvironment can be functionally inhibited and lose the ability of clonal proliferation due to depressed expression of CD25.     

Low incidence of TEL/AML1 fusion and TEL deletion in Korean childhood acute leukemia by extra-signal fluorescence in situ hybridization

TEL/AML1 fusion in acute leukemia results from cryptic translocation of chromosome 12 and 21, the presence of which suggests a favorable prognosis. The incidence of TEL/AML1 fusion in B-lineage ALL is approximately 25%, but the incidence in Korea has not yet been reported. To investigate the incidence of TEL/AML1 fusion and TEL deletion, bone marrow specimens from 77 Korean children with newly diagnosed acute leukemia were analyzed by FISH. We applied extra-signal FISH to discriminate a true TEL/AML1 fusion from a false-positive fusion signal. To determine the cut-off value of the TEL/AML1 fusion signal, 20 normal bone marrow specimens and 28 normal peripheral blood specimens were also analyzed. The frequency of patients with TEL/AML1 fusion was 13.3% (4 cases) among 30 B-lineage ALL and 9.5% among 42 ALL. One TEL/AML1 fusion-positive patient was also found among 4 acute biphenotypic leukemias. TEL/AML1 fusion was not found in any samples from patients with T-lineage ALL or AML. The incidence of TEL deletion was 6.7% (2 cases) among 30 B-lineage ALL and 4.8% among 42 ALL. The incidences of TEL/AML1 fusion and TEL deletion in Korean children with acute leukemia appear to be lower than those in other countries, suggesting a racial difference.     

High-level amplification of the RUNX1 gene in two cases of childhood acute lymphoblastic leukemia

The RUNX1 (alias AML1) gene is involved in several patterns of chromosomal translocations and rearrangements associated with human acute leukemia. Often, multiple signals for AML1 have been observed in childhood acute lymphoblastic leukemia (ALL) due to frequent polysomy of chromosome 21 in this leukemia. Additionally, high-level amplification of AML1, in the absence of polysomy of chromosome 21, has been reported in childhood ALL. We report two new cases of childhood ALL, without a ETV6/RUNX1 (alias TEL/AML1) rearrangement, showing high-level amplification of the AML1 gene detected by fluorescence in situ hybridization and comparative genomic hybridization analysis. The first case was an 11-year-old girl with 7–12 signals for AML1 in nearly 84% of the cells, and the loss of a TEL allele. In the second patient, a 6-year-old girl, multiple copies of the AML1 gene were also observed in 99% of the cells, although no deletion of TEL was found. The similarity in the clinicobiologic features of all the cases with this abnormality points to an emerging molecular cytogenetic subgroup of B-cell precursor ALL and suggests a possible dosage effect of AML1 in the pathogenesis of leukemia.     

Change in body weight after hormone replacement therapy in postmenopausal women is dependent on basal circulating leptin

Objective: To address the effect of leptin in the modulation of change in body weight after hormone replacement therapy (HRT), we prospectively examined the responses of body weight and serum leptin after estrogen–progestin replacement in postmenopausal women. Patients: Subjects consisted of 63 postmenopausal women aged 54–82 years on HRT for osteoporosis. Design: Thirty three of the subjects received 0.3 mg of conjugated equine estrogen (CEE) (group 1) while 30 were on 0.625 mg of CEE daily (group 2). All subjects also took 5 mg of medrogestone acetate and 750 mg elemental calcium supplement daily. Measurements: Fasting serum leptin was measured by RIA at baseline, 1 and 3 months after treatment. Data were expressed as mean±S.E.M. Results: Serum leptin was highly related to body weight both at baseline (r=0.40, P<0.001) and after 3 months of HRT (r=0.42, P<0.001). When divided the subjects into three equal groups according to baseline leptin levels, it was found that serum leptin significantly decreased in subjects with high baseline leptin at 3 months (−9.4±5.7%, P<0.05) while it increased in subjects whose baseline leptin levels were in the lowest tertile at 1 month (33.2±8.3%, P<0.001) and 3 month (27.8±8.3%, P<0.01). In regards to body weight, those with leptin in the highest tertile demonstrated a reduction of body weight at 3 (−1.9±0.6%, P<0.05) and 12 months (−3.2±0.5%, P<0.05) after HRT while those whose serum leptin levels were in the lowest and middle tertiles did not demonstrate change in body weight. By repeated measured analysis of variance, it was found that the decrease in body weight in subjects with high serum leptin was independent of the doses of estrogen. Conclusion: Postmenopausal hormone replacement does not cause weight gain. However, it results in a small reduction in body weight particularly in subjects with higher basal leptin concentrations.     

On the physical properties of red cell ghost membranes in the affective disorders and psychoses A fluorescence polarization study

Membrane order was measured in the erythrocyte ghost membranes of DSM-III schizophreniform disorder (SF), DSM-III schizophrenic (SCZ) and DSM-III manic (bipolar) (M) patients and a group of age- and sex-matched controls. Fluorescence polarization with the probe 1,6-diphenyl1-1,3,5-hexatriene was used to determine the steady-state fluorescence anisotropy (r_s). The SF group showed a significant increase in r_s (Δr_s = 0.037) from the control group. Although the means were not significantly different, 3 of 8 Ms and 5 of 8 SCZs also had r_s values > the highest control value. Thermotropic behavior of the membranes was evaluated over the range of 40 to 20°C. No difference among groups in membrane enthalpy was detected. Thus, the differences in r_s appear to be associated with differences in entropy. Phosphatidylcholine (PC) levels, which were known to be abnormal in these patients, were compared with the r_s values. A significant (P < 0.001, R= -0.63) linear correlation between r_s and membrane PC levels was observed. Overall these data further support the view that unusual membrane biophysical factors may occur with high frequency in the psychoses and affective disorders.     

Long-term effect of transdermal hormonal therapy on aspects of quality of life in postmenopausal women

The long-term effect on aspects of quality of life (QoL) of treatment with transdermal oestrogen for 2 weeks followed by transdermal oestrogen/progestogen norethisterone acetate/oestradiol TTS 0.25/0.05 mg/day for the next 2 weeks was investigated in postmenopausal women within the framework of a 1-year seven-centre trial. Of the 136 women who were included (mean age 53 ± 4.8 years), 110 completed the study. Aspects of QoL that are of relevance in the perimenopause and postmenopause were evaluated using the Psychological General Well-Being (PGWB) index, the Women's Health Questionnaire (WHQ) and the Sleep Dysfunction Scale before and after 3 and 9 months of therapy in the oestrogen phase. Climacteric complaints were also assessed by means of the Kupperman Index. Improved well-being, i.e. less anxiety and depression, increased vitality and better self-control (P < 0.0001) were observed, as well as reduced sleep disturbance (P < 0.0001). The WHQ showed decreased vasomotor and somatic symptoms, and improved sex life, emotions and cognitive function (P < 0.0001). Improvement was the same at 3 and 9 months. According to the Kupperman Index, climacteric symptoms were alleviated (P < 0.0001). Relief of vasomotor symptoms was correlated with improvement in the WHQ (r = 0.82), the PGWB index (r = 0.58, P < 0.0001) and sleep (r = 0.51, P < 0.0001). Because of the absence of a placebo control group, the results must be regarded with caution until confirmed in a placebo-controlled trial.     

Defects of natural killer cell activity in children with untreated acute lymphocytic leukemia

Summary Natural killer (NK) activity against cells of the K-562 line was significantly depressed in 12 of 18 children (66%) with untreated acute lymphocytic leukemia (ALL). No suppression of allogeneic NK activity was observed with sera of the patients, regardless of the level of NK depression. The ability of peripheral blood lymphocytes (PBLs) to suppress allogeneic NK activity was tested in two ALL patients — one with no detectable NK activity, and one with high NK activity. No NK-suppressive activity was found with PBLs of the areactive patient; PBLs of the reactive patients exhibited some suppressive activity, but only at a particular suppressor-to-effector cell ratio. Leukemic blasts were resistant to killing by autologous NK cells stimulated by IFN, as well as to killing by allogeneic, IFN-stimulated PBLs. Leukemic blasts of an ALL patient inhibited lysis of K-562 cells in an 18-h, but not in a 4-h NK assay. The inhibition could partly be reversed by pretreatment of ALL cells with alpha interferon, suggesting that the blasts might inhibit the lysis of K-562 targets in a competitive manner. Disturbed function and/or regulation of NK cells may influence attempts at NK cell activation by lymphokines.Abbreviations ALL acute lymphocytic leukemia - AML acute myeloid leukemia - CLL chronic lymphocytic leukemia - CML chronic myeloid leukemia - IFN interferon - IL-2 interleukin-2 - LGL large granular lymphocyte - NK cell natural killer cell - PBL peripheral blood lymphocyte - Poly I:C polyinosinic-polycytidylic acid     

Increased frequency of chromosomal damage in peripheral blood lymphocytes up to nine years following curative chemotherapy of patients with testicular carcinoma.

The presence of micronuclei (MN) in binucleated peripheral blood lymphocytes of 37 testicular carcinoma patients was studied 1.5 to 9.3 years following curative chemotherapy. All patients received cisplatinum, 35 patients also received bleomycin. In addition, most patients were treated with another cytotoxic drug, i.e., vinblastine (n = 23) and/or etoposide (n = 24). The mean time interval between cessation of chemotherapy and the micronucleus assay was 4.6 years. The median frequency of MN in binucleated cells in treated patients (0.059) was significantly higher than that in 12 untreated cancer patients (0.036; P = 0.003) or that in 26 healthy age-matched controls (0.034; P less than 0.001). Frequencies of MN in the 12 untreated cancer patients (including 7 patients with disseminated testicular carcinoma) did not differ from those in the 26 healthy controls (P = 0.890), suggesting that chromosomal damage in lymphocytes of treated testicular cancer patients must be attributed to the chemotherapy. Results indicate that lymphocytes containing chemically induced chromosomal damage persist for up to 9.3 years following cessation of chemotherapy. The implications of these findings with regard to the increased risk for secondary tumors are discussed.     

Effects of percutaneous oestradiol versus oral oestrogens on bone density

In order to compare the effects on bone density of 1.5 mg/day percutaneous 17β-estradiol (E₂) and of 0.625 mg/day oral conjugated oestrogens (CEE), 68 women who had undergone hysterectomy were studied. The subjects were randomly allocated to one of three study groups. A total of 15 women dropped out from these groups during the study. The percutaneous group (n = 20) received treatment for 36 months and the oral group (n = 17) for 24 months, while the untreated group (n = 16) served as controls over a period of 24 months. Bone mineral density (BMD) was measured by dual gammagraphic densitometry (Novo 22A densitometer) in the lumbar spine (L2-L4). The percentage gain in the percutaneous group was 1.7% ± 3.9% after 12 months, 5.6% ± 2.9% (P < 0.001) after 24 months and 4.7% ± 3.2% (P < 0.001) after 36 months. In the oral group the gain was 3.5% ± 13.0% after 12 months and 4.3% ± 9.2% (P < 0.001) after 24 months. In the untreated group the bone density loss was 6.6% ± 3.5% (P < 0.001) after 12 months and 9.1% ± 3.4% (P < 0.001) after 24 months. On the basis of our results we concluded that both 1.5 mg/day percutaneous E₂ and 0.625 mg/day oral CEE not only prevented bone loss but also increased BMD, as was confirmed by our findings after 36 and 24 months of treatment, respectively.     

Silent polymorphisms within the coding region of human sodium/hydrogen exchanger isoform-1 cDNA in peripheral blood mononuclear cells of leukemia patients: A comparison with healthy controls

We have examined the sequence of the cDNA encoding the sodium/hydrogen exchanger isoform 1 (NHE1), from 23 bases upstream of the start codon to 28 bases downstream of the stop codon. Template was prepared from (1) peripheral blood mononuclear cells (PBMC) isolated from 10 healthy unrelated Caucasian volunteers; (2) PBMCs isolated from 6 leukemic patients (acute lymphoblastic leukemia [ALL], n = 3; chronic lymphocytic leukemia [CLL], n = 1; chronic myelogenous leukemia [CML], n = 2); and (3) samples of 4 leukemic cell lines (ALL: CEM, MOLT4; AML: KG1a; CML: K562). NHE1 cDNA in normal PBMCs showed silent polymorphism of nucleotides 112 (N1: T, frequency 0.70; C, frequency 0.30; prevalence of heterozygosity 0.42); 2248 (N2: G, frequency 0.90; A, frequency 0. 10; heterozygosity 0.18); and 2493 (N3: G, frequency 0.90; A, frequency 0.10; heterozygosity 0.18). Deduced primary structure of NHE1 protein in all normal volunteers was identical to that previously published for NHE1 from renal and cardiac tissue. Similar to normal PBMCs, NHE1 cDNA from leukemic cells showed polymorphism of nucleotides N1, N2, and N3, but failed to demonstrate leukemia-specific sequence differences. We conclude that the coding region of NHE1 cDNA shows a greater level of polymorphism than is currently recognized, but that sequence mutation of NHE1 is not a key event in the pathogenesis of leukemia.     

Sister chromatid exchanges in leukemic patients

Sister chromatid exchange (SCE) was studied in PHA-stimulated peripheral blood lymphocytes from 36 newly diagnosed and untreated leukemic patients: 16 with acute lymphoblastic leukemia (ALL), 10 with acute nonlymphocytic leukemia (ANLL), and 10 with chronic myelocytic leukemia (CML). The metaphases analyzed show no chromosomal abnormalities. The mean SCE frequency (mean +/- SE) for each group of patients was: 6.8 +/- 0.4, 6.6 +/- 0.3, and 7.0 +/- 0.6 per mitosis, respectively, which was significantly lower than the mean SCE score for 30 controls (8.7 +/- 0.2). No differences in SCE score among ALL, ANLL, and CML and a similar SCE frequency by chromosome number and group allowed consolidation of all the cases into a single group of 36 leukemic patients (6.8 +/- 0.3). When the frequency of SCE was compared by chromosome number and group between the leukemic patients with the control group, a significant decrease in SCE frequency was observed due to a low SCE score in almost all the complements, except chromosome #1. It is suggested that the low SCE rate is related to the leukemic process itself.     

Diurnal preference, sleep habits, circadian sleep propensity and melatonin rhythm in healthy human subjects

After 24-h sleep deprivation, 33 healthy young subjects entered the 10/20 min ultra-short sleep–wake schedule for 26 h. Melatonin rhythm was hourly assessed simultaneously. Results indicated that morning preference was significantly correlated with habitual sleep onset (r=−0.41, P=0.04), habitual sleep offset (r=−0.52, P=0.002), melatonin peak time (r=−0.36, P=0.04), and sleep propensity onset time (r=−0.36, P=0.04). The intervals between habitual sleep mid-point and melatonin peak time and between habitual sleep mid-point and sleep propensity onset time were significantly longer in morning-preference subjects than in evening-preference subjects (P<0.05). These findings suggest that the variance of diurnal preference may be related to differences in phase relations between habitual sleep timing and the circadian pacemaker.     

Prophylaxis of osteoporosis with calcium, estrogens and/or eelcatonin: comparative longitudinal study of bone mass

Objective: To evaluate three different therapeutic regimens for the prevention of osteoporosis in natural and surgical postmenopausal women who had been found to have rapid bone loss in analytical studies. Methods: A total of 104 naturally or surgically postmenopausal women were studied, and subsequently followed-up during 1 year for avoidance of the influence of seasonal variation on bone mass, a factor overlooked in several studies. They were randomized into four groups of 26 patients each: the untreated control group (mean age 50 ± 5 years); the hormonal replacement treatment (HRT) group (mean age 48 ± 6 years), which was treated for 24 days each month with transdermal 17β-estradiol, 50 mg/day, together with medroxiprogesterone, 10 mg during 12 days; the calcium group (mean age 50 ± 4 years), which was treated with elemental calcium, 1 g/day; and the calcitonin group (mean age 50 ± 5 years), which was treated for 10 days each month with eel calcitonin, 40 IU/day and with elemental calcium, 500 mg/day. Full-body bone densitometry, for measuring total body bone mineral content (TBBMC), was carried out in all the women at baseline and 1 year. TBBMC was corrected for body weight by dividing its value by body weight (TBBMC/W). Results: After 1 year TBBMC/W was lower in every group: −2.14% (P < 0.001) in the control group; −0.14% (P = NS) in the HRT group (P < 0.05 vs. controls); −0.18% (P = NS) in the calcium group (P < 0.05 vs. controls); and −0.06% (P = NS) in the calcitonin group (P < 0.01 vs. controls; P < 0.05 vs. calcium and HRT). Conclusions: These findings show that all three treatments are effective in the prevention of postmenopausal loss of bone mass.     

TNR/11q#1 Trinucleotide (GCC)n Repeat Alleles and Predisposition to Acute and Chronic Leukemia

TNR/11q#1 is a polymorphic trinucleotide (GCC)n repeat located within the minimal region of the 11q deletion in chronic lymphocytic leukemia (CLL). It was recently shown that certain alleles of this repeat are associated with a worse prognosis in CLL patients. To investigate the role of TNR/11q#1 variants as risk‐modifying factors in leukemogenesis, we conducted a case‐control study on 113 acute lymphotic leukemia (ALL) patients, 82 CLL patients and 146 healthy controls of Russian origin. Comparison of allele and genotype distributions in the control, ALL and CLL groups, performed by Fisher's exact test with two‐sized P‐value, showed significant decrease in the presence of the GCC₆ allele in the ALL and CLL groups compared to controls. Moreover, ‘rare' alleles GCC_7‐8 and GCC_13‐14 were significantly overrepresented in the ALL group versus controls. We found that CLL risk genotypes were those with both alleles containing more than 6 GCC repeats (P = 0,0212, odds ratio = 1,68 (95% CI, 1 121… 2,531)). ALL risk genotypes include three allele combination variants: 1) both alleles containing more than 6 GCC repeats (P = 0,0019, odds ratio = 1,756 (95% CI 1,223…2,502)); 2) one of the alleles containing 7 or 8 repeats (P = 0,0155, odds ratio = 18,22 (95% CI 1,93…136.37)); 3) one of the alleles containing more than 12 repeats (P = 0,0209, Odds ratio = 2,599 (95% CI 1,161…5,815)). Association of certain alleles and genotypes of the TNR/11q#1 repeat with both acute and chronic lymphocytic leukemia suggests the presence of a cancer related gene, involved in a wide spectrum of neoplasia, in the vicinity of this repeat.