The fluctuating phenotype of the lymphohematopoietic stem cell with cell cycle transit.

The most primitive engrafting hematopoietic stem cell has been assumed to have a fixed phenotype, with changes in engraftment and renewal potential occurring in a stepwise irreversible fashion linked with differentiation. Recent work shows that in vitro cytokine stimulation of murine marrow cells induces cell cycle transit of primitive stem cells, taking 40 h for progression from G0 to mitosis and 12 h for subsequent doublings. At 48 h of culture, progenitors are expanded, but stem cell engraftment is markedly diminished. We have investigated whether this effect on engraftment was an irreversible step or a reversible plastic feature correlated with cell cycle progression. Long-term engraftment (2 and 6 mo) of male BALB/c marrow cells exposed in vitro to interleukin (IL)-3, IL-6, IL-11, and steel factor was assessed at 2-4-h intervals of culture over 24-48 h using irradiated female hosts; the engraftment phenotype showed marked fluctuations over 2-4-h intervals, with engraftment nadirs occurring in late S and early G2. These data show that early stem cell regulation is cell cycle based, and have critical implications for strategies for stem cell expansion and engraftment or gene therapy, since position in cell cycle will determine whether effective engraftment occurs in either setting.

The N-terminal 178-amino-acid domain only of the SV40 large T antigen acts as a transforming suppressor of the HER-2/neu oncogene.

The deregulation of the HER-2/neu protooncogene was demonstrated in a wide variety of human cancers and shown to be correlated with the progress of malignancy and metastasis in animal models. Repression of HER-2/neu overexpression suppressed the malignant phenotypes of HER-2/neu-overexpressing cancer cells. This suggested that HER-2/neu may be a good target for developing anti-cancer drugs. We found a deletion mutant of simian virus 40 (SV40) large T antigen (LT) suppresses the HER-2/neu oncogene expression at the transcriptional level. PCR clones of this mutant SV40LT, named LT425, which contains the N-terminal region of amino acid residues 1-178 of SV40LT, were subcloned and stably transfected into the HER-2/neu-overexpressing human ovarian cancer SKOV3.ip1 cells. These LT425 clones were found to be able to down-regulate the endogenous production of p185(HER-2/neu). In addition, the LT425-expressing stable transfectants showed reduced growth rate, low soft agarose colony forming ability, and low tumorigenic potential as compared with the parental line. These data suggested that the N-terminal 178 amino acids domain only of SV40LT may act as a transforming repressor of HER-2/neu oncogene.

MRI-derived entorhinal volume is a good predictor of conversion from MCI to AD.

With high-resolution quantitative magnetic resonance imaging (MRI) techniques, it is possible to examine alterations in brain anatomy in vivo and to identify regions affected in the earliest stages of Alzheimer's disease (AD). In the present study, 27 patients diagnosed with mild cognitive impairment (MCI) received a high-resolution MRI scan at baseline and were followed with yearly clinical evaluations. Ten of the 27 patients converted to AD during a 36-month period following the baseline clinical evaluation. Hippocampal and entorhinal cortex volumes derived from the baseline scan were compared to determine which of these two regions, known to be pathologically involved very early in the course of AD, could best differentiate MCI converters from non-converters. Although both entorhinal and hippocampal volumes were found to be independent predictors of the likelihood of conversion to AD, it was the right hemisphere entorhinal volume that best predicted conversion with a concordance rate of 93.5%.

Duration of gestation and prostate cancer risk in offspring.

This large population-based nested case-control study investigated the importance of perinatal characteristics as risk factors for prostate cancer in later life in a cohort of men who were born between 1889 and 1941 in Stockholm, Sweden. Eight hundred and thirty-four prostate cancer cases over 18 years of age and of singleton birth were identified from the cohort between 1958 and 1994. For each case, singleton males born live to the first four mothers admitted after the case's mother were selected as potential controls; 1880 eligible controls were included in the study. For each study subject, we obtained data on mother's parity, pre-eclampsia or eclampsia before delivery, age at delivery, and socioeconomic status, as well as child's birth length and weight, placental weight, and gestational age. Odds ratio (OR) estimates and 95% confidence intervals (CIs) were derived from logistic regression analyses. We found no statistically significant differences between cases and controls with respect to maternal age, socioeconomic status, or parity. Birth weight, birth length, and placental weight were also not significantly related to prostate cancer risk. Pregnancy toxemia (OR = 0.33; 95% CI, 0.07-1.45) and longer gestation age were associated with a reduced risk of prostate cancer; the OR estimate was 0.94 (95% CI, 0.89-0.99) for each 1-week prolongation of the duration of gestation. Our results suggest that birth size indicators are not important risk factors for prostate cancer in later life. In addition, our data on gestation age indicate that the late in utero environment may be as important as the early in utero environment in the modulation of prostate cancer risk in offspring.

Huntington's disease: a randomized, controlled trial using the NMDA-antagonist amantadine.

OBJECTIVE: To examine the acute effects of the NMDA receptor antagonist amantadine on motor and cognitive function in Huntington's disease (HD). BACKGROUND: Chorea in HD and in the levodopa-induced dyskinesias of PD may be clinically indistinguishable. In PD, hyperphosphorylation of NMDA receptors expressed on striatal medium spiny neurons contributes to peak-dose dyskinesias, and drugs that block these receptors can diminish chorea severity. Because these spiny neurons are the primary target of the neurodegenerative process in HD, sensitization of NMDA receptors on residual striatal neurons might also participate in the generation of motor dysfunction in HD. METHODS: To evaluate this possibility, 24 patients with HD entered a double-blind placebo-controlled crossover study of amantadine with two 2-week arms. RESULTS: Chorea scores were lower with amantadine (usually 400 mg/d) than placebo, with a median reduction in extremity chorea at rest of 36% (p = 0.04) for all 22 evaluable patients and of 56% in the 10 individuals with the highest plasma drug levels. Improvement correlated with plasma amantadine concentrations (p = 0.01) but not CAG repeat length. Parkinsonian rating scores did not worsen and there was no consistent change in cognitive measures. Adverse event profile was benign. CONCLUSIONS: Results suggest that NMDA receptor supersensitivity may contribute to the clinical expression of choreiform dyskinesias in HD and that selective antagonists at that site can safely confer palliative benefit.

Coexpression of granulocyte colony stimulating factor and its receptor in primary ovarian carcinomas.

Immunohistochemistry was used to determine the expression of granulocyte colony-stimulating factor (G-CSF) and its receptor (G-CSFR) in primary ovarian carcinomas. The expression of G-CSFR was observed in the malignant cells of each of the 46 primary carcinomas examined; G-CSF was coexpressed in both the malignant epithelial cells and the stroma of 56.5% of the specimens. Thus the majority of ovarian carcinomas harbor both potential autocrine and paracrine G-CSF axes. In 37% of the samples, G-CSF was expressed only within stromal cells, suggesting that only a potential paracrine system is in place. In a preliminary, retrospective, evaluation, the survival of patients whose tumors expressed only the apparent paracrine loop was significantly worse than patients whose tumors expressed both potential autocrine and paracrine G-CSF-based regulatory loops (14.5 vs. 42.5 months, respectively). Studies on the potential function of G-CSF were performed using the G-CSFR-expressing OVCAR-3 ovarian carcinoma line. As a single agent, rhG-CSF failed to stimulate [3H]-thymidine incorporation in these cells, but enhanced the mitogenic action of epidermal growth factor (EGF) in a dose-dependent manner. Thus, potential autocrine and/or paracrine loops involving G-CSF and its receptor occur in over 90% of primary ovarian carcinomas, and may act to modulate the action of growth factors.

The role of cell cycle regulatory proteins, cyclin D1, cyclin E, and p27 in thyroid carcinogenesis.

The cell cycle is controlled in part by cyclin-dependent kinases (CDKs), which are activated by forming complexes with cyclins. CDKs phosphorylate certain substrates to facilitate the proliferating cells through the cell cycle. CDK inhibitors (CDKIs) such as p27 inhibit cyclin-CDK complexes and function as a negative cell cycle regulator. The overexpression of the positive regulators (cyclins) or the underexpression of the negative regulators including p27 has been seen in a variety of neoplasms, but their role and interaction in thyroid carcinogenesis is yet to be established. We studied the expression of cyclins D1 and E, and the CDKI, p27 by immunohistochemistry in 116 cases, including 59 cases of follicular variant of papillary carcinoma (FVPC) and 57 cases of follicular adenoma (FA). The positive staining was divided into four grades: 1+ if less than 10%, 2+ if 11% to 25%, 3+ if 26% to 50%, and 4+ if greater than 50% of the nuclei of tumor cells stained positively. Cyclin D1 expression was seen in 37 (63%) FVPC and 34 (60%) FA. Cyclin E-positive cells were seen in 51 (86%) FVPC and 47 (82%) FA. No significant differences in the grade of cyclins D1 (P = .261) and E (P = .284) staining was seen between FVPC and FA. Of the 59 FVPC, 53 (89%) showed p27-positive cells; of these, 33 were 1+, nine were 2+, seven were 3+ and only four were 4+ positive. Conversely, all 57 FA were p27 positive, 53 were 4+, and four were 3+ positive. This difference in the grade of p27 staining between FVPC and FA was statistically significant (P < .001). This study shows a significant underexpression of p27 in FVPC compared with FA, suggesting that a decrease in p27 expression plays a more important role than overexpression of cyclins D1 and E alone in thyroid carcinogenesis and that p27 immunostaining may be helpful in the diagnosis of FVPC.

Bigger is better: maternal and neonatal predictors of hematopoietic potential of umbilical cord blood units.

Umbilical cord blood (CB) is a useful stem cell source for patients without matched family donors. CB banking is expensive, however, because only a small percentage of the cord units stored are used for transplantation. In this study, we determined whether maternal factors, such as race, age, and smoking status have an effect on laboratory parameters of hematopoietic potential, such as viability, cell counts, CD34+ cell counts, and CFU-GM. We studied the effect of neonatal characteristics such as birth order, birth weight, gestational age, and sex of the baby on the same laboratory parameters. Race and maternal age had no effect on these laboratory parameters. In multivariate analysis, babies of longer gestational age had higher cell counts, but lower CD34+ cell counts and CFU-GM. Bigger babies had higher cell counts, more CD34+ cells, and more CFU-GM. Women with fewer previous live births also produced cord units with higher cell counts, CFU-GM, and CD34+ cell counts. Specifically, each 500 g increase in birth weight contributed to a 28% increase in CD34+ cell counts, each week of gestation contributed to a 9% decrease in CD34+cell counts, and each previous birth contributed to a 17% decrease in CD34+ cell counts (all P < 0.05). These data may be used to select the optimal cord blood donors and allow CB banks efficient resource allocation.

Clearance kinetics of CD34+ cells from peripheral blood: an independent predictor of hematologic recovery after high-dose chemotherapy and hematopoietic stem cell transplantation.

We measured the concentration of CD34+ cells in peripheral blood (PB) (1/2) h prior to and (1/2), 1, 3, 6, and 12 h following hematopoietic stem cell (HSC) infusion in 34 breast cancer patients treated with high-dose chemotherapy (HDC). The decrease in these concentrations over time enabled us to determine the clearance kinetics of CD34+ cells from PB. The absolute number of CD34+ cells in PB generally peaked at (1/2) h after infusion, then rapidly declined from 1 to 3 h post infusion and continued to fall until 12 h post transplant, but more slowly. In univariate analysis, CD34+cells/kg infused, CFU-GM/kg infused, the CD34+ count at (1/2) h, and the 12-h clearance of CD34+ cells from PB were predictors of hematologic recovery, as were each of the two phases of clearance when the slope was divided into rapid and slow phases (from (1/2) to 3 and from 3 to 12 h post transplant, respectively). We then stratified our population by the number of CD34+ cells/kg infused. In group 1, patients received 7.5 x 10(6) CD34+ cells/kg. After adjusting for CD34+ cells injected, age, and purged or unpurged graft in multivariate analysis, the 12 h clearance remained a predictor of hematologic recovery in group 1. In addition, the second phase of clearance (from 3 to 12 h after infusion) was an even better predictor than the 12 h clearance. In group 2, however, no statistically significant correlation was observed, even with the number of HSC injected. Results suggest that rapidity of clearance of CD34+cells from PB is an independent indicator of hematologic recovery in patients receiving lower doses of CD34+ cells. When the cell dose injected is over a threshold, PB clearance correlations with hematologic recovery are masked.

Influence of timing of administration of 5-fluorouracil to donors on bone marrow engraftment in nonmyeloablated hosts.

We evaluated the engraftment and the cell cycle status of marrow cells at various times after 5-fluorouracil (5-FU) administration. 5-FU (150 mg/kg) was given to donor male BALB/c mice at 1, 2, 6, or 12 days prior to marrow harvest. The donor cells were then assessed in host nonmyeloablated female mice. Bone marrow engraftment of marrow treated with 5-FU was evaluated and compared to marrow treated with diluent (phosphate-buffered saline) at 3 and 10 weeks after marrow infusion. Our data show a rapid induction of an engraftment defect 1 day after 5-FU, persistence of this defect through day 6, and a recovery by day 12. Experiments using hydroxyurea (which selectively kills cells in the S phase) to determine the cell cycle status indicated that cells that engrafted in post-5-FU marrow were noncycling at days 1, 2, and 12 but cycling at day 6. Post-5-FU bone marrow was also analyzed in vitro by colony assays and its cycling status determined by 3H-thymidine suicide assay. High-proliferative-potential colony-forming cells (HPP-CFCs) and low-proliferative-potential colony-forming cells (LPP-CFCs) decreased rapidly 1 day after 5-FU, with a nadir observed at day 6 for HPP-CFCs and day 2 for LPP-CFCs. By day 12, LPP-CFCs showed a total recovery, but HPP-CFCs were still defective. Significant numbers of HPP-CFCs were cycling, mostly at days 6 and 8 after 5-FU, whereas LPP-CFCs appeared quiescent except at day 2. These results emphasize the importance of timing if post-5-FU marrow is used for gene therapy or marrow transplantation.

Lifestyle factors and insulin-like growth factor 1 levels among elderly men.

Insulin-like growth factor 1 (IGF-1) is a potentially important determinant of disease; hence epidemiological identification of factors that influence circulating IGF-1 is merited. We therefore analysed data collected in Greece to determine the relationship between anthropometric, lifestyle and dietary variables and serum levels of IGF-1 among elderly men. We identified 51 men with prostate cancer, 50 men with benign prostatic hyperplasia, and 52 apparently healthy elderly men (controls), all matched for age (+/- 1 year). These 153 men provided blood specimens and were interviewed using a validated lifestyle and food frequency questionnaire. We performed multivariate linear regression to identify potential predictors of circulating IGF-1. After controlling for age, body mass index, smoking habits, alcohol drinking and coffee consumption, each 5 cm increase in height predicted a 13.0% increase in IGF-1 (95% CI 0.4-27.2%) among the controls and a 11.3% increase in IGF-1 (95% CI 4.5-18.6%) among the entire study group. None of the investigated dietary factors (total fat, carbohydrate, protein, dairy products, tomatoes, calcium) were strongly related to IGF-1 levels. The positive association between IGF-1 and height integrates the empirical evidence linking IGF-1 and height with prostate cancer risk.

Correlates of pregnancy oestrogen, progesterone and sex hormone-binding globulin in the USA and China.

The objective of this study is to examine perinatal correlates of oestradiol (E2), oestriol (E3), progesterone and sex hormone-binding globulin (SHBG) among pregnant women in the USA and China. Three hundred and four Caucasian women in Boston and 335 Chinese women in Shanghai were studied. Levels of E2, E3, progesterone and SHBG were measured in maternal blood at weeks 16 and 27 of gestation, and correlated with maternal, gestational and perinatal characteristics. Height, weight and body mass index (BMI) before pregnancy is inversely associated with E2 and SHBG, whereas E3 is inversely associated with height and progesterone is inversely associated with weight and BMI. A previous live birth is associated with lower E2 and SHBG in the index pregnancy. Total gestation duration is inversely associated with E2, E3 and progesterone, whereas weight gain during pregnancy is inversely associated with progesterone and SHBG. In the US, pregnancies with female fetuses are characterized by significantly reduced progesterone. Pregnancy hormones are associated with several maternal, gestational and neonatal characteristics.

Maternal and gestational correlates of pregnancy prolactin and growth hormone in USA and China.

The objective of this study is to determine correlates of prolactin and growth hormone levels among pregnant women in the USA and China. We studied 304 pregnant Caucasian and 335 pregnant Chinese women. Levels of prolactin and growth hormone were measured at weeks 16 and 27 of gestation, and correlated with maternal, gestational and perinatal characteristics. Both growth hormone and, to a lesser extent, prolactin were inversely associated with pregnancy weight and body mass index, history of a previous live birth and newborn size, whereas educated women had higher levels of both hormones. Growth hormone levels were lower in women who gained more weight, smoked and had nausea and vomiting during pregnancy, whereas prolactin increased with longer total gestation. We found robust associations between maternal and newborn characteristics on the one hand and prolactin and growth hormone during pregnancy on the other.

Frequency and Distribution of DNA fragmentation in Hashimoto's thyroiditis and development of papillary thyroid carcinoma.

Downregulation of apoptosis and high expression of bcl-2 play an important role in the development of follicular lymphoma. However, little is known about apoptosis in thyroid disease, particularly with respect to the development of papillary carcinoma from Hashimoto's thyroiditis. To study the early stages of cell death in various types of thyroid disease, surgical specimens from 31 patients including Hashimoto's thyroiditis (HT,n=7), papillary carcinoma (PC,n=12), Hashimoto's thyroiditis with papillary carcinoma (HTPC,n=5), and Graves' disease (GD,n=7) were examined by anin situ nucleotidyl transferase assay (ISNTA), which detects DNA fragmentation. Control normal thyroid tissue (NT,n=7) was obtained from surgically resected papillary thyroid carcinomas sampled away from the primary tumor. An immunohistochemical (IHC) method was used to detect bcl-2 expression. Positive ISNTA nuclei in thyroid follicular cells or tumor cells per section were counted in all parenchymal areas, excluding areas of lymphocyte aggregates. The intensity of bcl-2 staining was graded on a scale of 1+ to 3+. The number of ISNTA-positive thyroid follicular cells was a significantly higher in HT compared to GD. In addition, there was significantly lower number of ISNTA positive non-neoplastic thyroid follicular cells in HTPC compared to HT alone. Strong expression of bcl-2 was found in all cases of GD and NT, but much less bcl-2 staining was seen in HT. There was moderate expression of bcl-2 in HTPC and PC. These findings suggest that (1) DNA fragmentation of the thyroid follicular cells plays an important role in the thyroid injury in HT but not in GD, (2) expression of bcl-2 may overcome the apoptosis in GD but not in HT, and (3) downregulation of DNA fragmentation of the follicular cells in Hashimoto's thyroiditis associated with papillary carcinoma may suggest an important mechanism for tumor pathogenesis.

Isolation and characterization of a newly identified type II restriction endonuclease from a local Streptomyces sp. in Taiwan.

Streptomyces chusanensis ZS-2, isolated from a soil sample in Chusan in Taiwan, was found to produce a new Type II restriction endonuclease. This restriction enzyme was designated as SchI. The purified enzyme was characterized as having a subunit mol wt of 28 kDa, and was apparently free from exonuclease activities. It cleaves the phosphodiester bond between the fourth C and the fifth G on the 5'-CCGCGG-3' sequence of DNAs, leaving a 2-nucleotide protruding end at its 3' site. This data suggests that SchI is an isoschizomer of SacII. In addition, based on the comparison between SchI and SacII regarding reaction parameters, it seems that SchI is a better choice of restriction enzyme for genetic analysis and mapping.

Presymptomatic spinal cord neurometabolic findings in SOD1-positive people at risk for familial ALS.

OBJECTIVE: It has been speculated that amyotrophic lateral sclerosis (ALS) is characterized by a premanifest period during which neurodegeneration precedes the appearance of clinical manifestations. Magnetic resonance spectroscopy (MRS) was used to measure ratios of neurometabolites in the cervical spine of asymptomatic individuals with a mutation in the SOD1 gene (SOD1+) and compare their neurometabolic ratios to patients with ALS and healthy controls. METHODS: A cross-sectional study of (1)H-MRS of the cervical spine was performed on 24 presymptomatic SOD1+ volunteers, 29 healthy controls, and 23 patients with ALS. All presymptomatic subjects had no symptoms of disease, normal forced vital capacity, and normal electromyographic examination. Relative concentrations of choline (Cho), creatine (Cr), myo-inositol (Myo), and N-acetylaspartate (NAA) were determined. RESULTS: NAA/Cr and NAA/Myo ratios are reduced in both SOD1+ subjects (39.7%, p = 0.001 and 18.0%, p = 0.02) and patients with ALS (41.2%, p < 0.001 and 24.0%, p = 0.01) compared to controls. Myo/Cr is reduced (10.3%, p = 0.02) in SOD1+ subjects compared to controls, but no difference was found between patients with ALS and controls. By contrast, NAA/Cho is reduced in patients with ALS (24.0%, p = 0.002), but not in presymptomatic SOD1+ subjects compared to controls. CONCLUSIONS: Changes in neurometabolite ratios in the cervical spinal cord are evident in presymptomatic SOD1+ individuals in advance of symptoms and clinical or electromyographic signs of disease. These changes reflect a reduction in NAA/Cr and NAA/Myo. Neurometabolic changes in this population resemble changes observed in patients with clinically apparent ALS. This suggests that neurometabolic changes occur early in the course of the disease process.

Precuneus amyloid burden is associated with reduced cholinergic activity in Alzheimer disease.

OBJECTIVE: This study examined the relationship between postmortem precuneus cholinergic enzyme activity, Pittsburgh compound B (PiB) binding, and soluble amyloid-ß concentration in mild cognitive impairment (MCI) and Alzheimer disease (AD). METHODS: Choline acetyltransferase (ChAT) activity, [(3)H]PiB binding, and soluble amyloid-ß(1-42) (Aß42) concentration were quantified in precuneus tissue samples harvested postmortem from subjects with no cognitive impairment (NCI), MCI, and mild AD and correlated with their last antemortem Mini-Mental State Examination (MMSE) score and postmortem pathologic evaluation according to the National Institute on Aging-Reagan criteria, recommendations of the Consortium to Establish a Registry for Alzheimer's Disease, and Braak stage. RESULTS: Precuneus ChAT activity was lower in AD than in NCI and was comparable between MCI and NCI. Precuneus [(3)H]PiB binding and soluble Aß42 levels were elevated in MCI and significantly higher in AD than in NCI. Across all case subjects, reduced ChAT activity was associated with increased [(3)H]PiB binding, increased soluble Aß42, lower MMSE score, presence of the APOE*4 allele, and more advanced AD pathology. CONCLUSIONS: Despite accumulating amyloid burden, cholinergic enzyme activity is stable in the precuneus during prodromal AD. A decline in precuneus ChAT activity occurs only in clinical AD, when PiB binding and soluble Aß42 levels are substantially elevated compared with those in MCI. Anti-amyloid interventions in MCI case subjects with a positive PiB PET scan may aid in reducing cholinergic deficits and cognitive decline later in the disease process.

A lifetime psychiatric history predicts a worse seizure outcome following temporal lobectomy.

PURPOSE: To identify the psychiatric and epilepsy variables predictive of postsurgical seizure outcome after anterotemporal lobectomy (ATL). METHODS: Retrospective study of 100 consecutive patients with temporal lobe epilepsy (TLE) who underwent ATL. The mean (+/- SD) follow-up period was 8.3 (+/- 3.1) years. Three types of surgical outcomes were examined at 2 years after surgery and at last contact: class IA (no disabling seizures no auras), class IA + IB (no disabling seizures), and class IA + IB + IC (no or rare disabling seizures in the first postsurgical year). Logistic regression analyses were performed separately for the three types of surgical outcomes. The epilepsy-related independent variables included age at onset, cause of TLE (mesial temporal sclerosis, lesional and cryptogenic TLE), extent of resection of mesial structures, neuropathologic abnormalities, having only complex partial seizures, and duration of the seizure disorder. The psychiatric independent variables included a postsurgical and presurgical lifetime history of mood, anxiety, attention deficit hyperactivity, and psychotic disorders. RESULTS: The absence of a psychiatric history was an independent predictor of all three types of surgical outcomes. In addition, a larger resection of mesial structures was a predictor for class IA outcome, and having only complex partial seizures (vs generalized tonic-clonic seizures) was a predictor for class IA + IB and IA + IB + IC. Having mesial temporal sclerosis (vs other causes of TLE) was a predictor for class IA + IB + IC as well. CONCLUSIONS: These data indicate that a lifetime psychiatric history may be predictive of a worse postsurgical seizure outcome after an anterotemporal lobectomy.

Effect of donepezil on motor and cognitive function in Huntington disease.

Striatal cholinergic dysfunction may be important in Huntington disease (HD). We studied whether donepezil improves chorea, cognition, and quality of life (QoL) in HD. Thirty patients were randomly assigned to treatment with donepezil or placebo. At the doses studied, donepezil did not improve chorea, cognition, or QoL. Adverse events were similar between both groups. Based on this small sample study, donepezil was not an effective treatment for HD.

Childbearing at older age and endometrial cancer risk (Sweden).

OBJECTIVES: Several studies have found an inverse association between older age at last birth and endometrial cancer risk. A nested case-control study was undertaken to examine the influence of this and other aspects of reproductive patterns on the risk of developing endometrial cancer. METHODS: Among women born in 1925 and later, 4,839 eligible patients were identified in the Swedish Cancer Register. For each case, five individually age-matched controls were randomly selected from a population-based Fertility Register. Relative risks were estimated from odds ratios obtained from conditional logistic regression analyses. RESULTS: Compared to uniparous women, childless women were at a higher risk of endometrial cancer (odds ratio [OR] = 1.38, 95% confidence interval [CI] = 1.25-1.52). This association was stronger in younger (< 50 years) than in older (50+ years) women. At all ages of first birth, a delivery was associated with a reduced risk of endometrial cancer that slowly diminished with time. Among parous women, the risk decreased by almost 20% for each additional live birth (OR = 0.81, CI = 0.78-0.84). In an analysis limited to women with two or more births that compared the independent effects of age at first and at last birth, only older age at last birth was associated with a lowered risk of endometrial cancer. The risk decreased at a rate of about 15% per five-year delay of last birth. CONCLUSIONS: Endometrial cancer is often referred to as the prototype hormonally-determined disease in women. However, our findings give further support to the hypothesis that a birth may not only affect risk through hormonal influences, but possibly also through mechanical shedding of cells that have undergone malignant transformation.