Phosphorylation of retinoid X receptor alpha at serine 260 impairs its metabolism and function in human hepatocellular carcinoma

Retinoids induce apoptosis and differentiation of hepatocellular carcinoma (HCC) cells and are used clinically in the chemoprevention of HCC. We have shown previously that hepatocarcinogenesis is accompanied by accumulation of full-length retinoid X receptor alpha (RXRalpha), although the underlying mechanisms and biological implications have remained unclear. The present studies were based on the finding that the accumulated full-length RXRalpha was phosphorylated at serine/threonine residues both in all human HCC tissues examined and in human HCC-derived HuH7 cells. Phosphorylation at serine 260 of RXRalpha, a consensus site of mitogen-activated protein kinase, was closely linked to its retarded degradation, low transactivating activity, and the promotion of cancer cell growth. There was no genomic mutation in the RXRalpha gene, and abrogation of phosphorylation by mitogen-activated protein kinase-specific inhibitors restored the degradation of RXRalpha in an RXR ligand-dependent manner. These results suggest that phosphorylation of RXRalpha may interfere with its metabolism and signaling in human HCC, which could lead to growth promotion of these tumors.     

Second malignant neoplasms in five-year survivors of childhood cancer: childhood cancer survivor study

BACKGROUND: Because survival rates among childhood cancer patients are increasing, assessing the risk of second and subsequent malignant neoplasms (SMNs) is ever more important. Using the Childhood Cancer Survivor Study cohort, we identified the risk of SMNS: METHODS: A retrospective cohort of 13 581 children diagnosed with common cancers before age 21 years and surviving at least 5 years was constructed with the use of data from patients treated at 25 U.S. and Canadian institutions. SMNs were ascertained through self-administered questionnaires and verified by pathology reports. Information on therapeutic exposures was abstracted from medical records. The risk of SMN was evaluated by standardized incidence ratios (SIRs) and excess absolute risk. Poisson multiple regression models were used to assess the impact of host and therapy factors on the risk of developing SMNS: All statistical tests were two-sided. RESULTS: In 298 individuals, 314 SMNs were identified (SIR = 6.38; 95% confidence interval [CI] = 5.69 to 7.13). The largest observed excess SMNs were bone and breast cancers (SIR = 19.14 [95% CI = 12.72 to 27.67] and SIR = 16.18 [95% CI = 12.35 to 20.83], respectively). A statistically significant excess of SMNs followed all childhood cancers. In multivariate regression models adjusted for therapeutic radiation exposure, SMNs of any type were independently associated with female sex (P<.001), childhood cancer at a younger age (P for trend <.001), childhood Hodgkin's disease or soft-tissue sarcoma (P<.001 and P =.01, respectively), and exposure to alkylating agents (P for trend =.02). Twenty years after the childhood cancer diagnosis, the cumulative estimated SMN incidence was 3.2%. However, only 1.88 excess malignancies occurred per 1000 years of patient follow-up. CONCLUSIONS: Success in treating children with cancer should not be overshadowed by the incidence of SMNS: However, patients and health-care providers must be aware of risk factors for SMNs so that surveillance is focused and early prevention strategies are implemented.     

Three-dimensional structure of the Hospital Anxiety and Depression Scale in a large French primary care population suffering from major depression.

Few studies have been specifically carried out to characterize the dimensional structure of the Hospital Anxiety and Depression Scale (HADS) and those that have, have yielded contradictory results. We have examined the factor structure and sensitivity to change of the HADS in a large French outpatient primary care population treated with sertraline for major depression (DSM-IV criteria). Factor analysis of the HADS was performed in 2669 outpatients and in subsamples using a principal component procedure with Varimax rotation. Concurrent change sensitivity of the HADS was compared with that for the Hamilton Depression Rating Scale (HDRS) after at least 45 days of sertraline treatment. Three distinct factors emerged from the HADS factor analysis: a "depression" factor and two separate anxiety subscales: "psychic anxiety" and "psychomotor agitation" whose mean reductions in scores from baseline were significantly correlated (0.36-0.45) with the reduction of the HDRS baseline score. These new data provide support for the use of the HADS's three-dimensional structure to measure improvement of selected symptoms of anxiety during antidepressant therapy.     

Dystonia and its disorders

Dystonia is a movement disorder characterized by sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. The term dystonia does not signify a single disease, but instead describes a symptom and sign that may be part of many disorders with a variety of causes. Dystonia may be classified by age of onset, distribution of symptoms, or by etiology. An increasing number of genetic forms of dystonia have been recognized and the findings have advanced knowledge of underlying neural mechanisms of pathogenesis. Options for treatment of dystonia include pharmacological therapy, botulinum toxin injection, or neurosurgical procedures.     

Predictors of depressive symptoms among spouse caregivers in Parkinson's disease.

The objective of this work was to determine the predictors of depressive symptoms among spouse caregivers of Parkinson's disease (PD) patients. Little is known about the strain in giving care to PD patients and how the motor, cognitive, and behavioral complications of PD contribute to depression among spouse caregivers. Forty-five consecutive PD patients and their spouse caregivers agreed to be evaluated after a routine clinic visit. Patient demographic data and the presence of hallucinations, delusions, incontinence, and sleep disturbances were obtained. The patients were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS-motor section), Hoehn and Yahr (H&Y) staging, and the Mini-Mental State Examination (MMSE). Depressive symptoms were assessed using the 17-item Hamilton Depression Scale (HAMD-17) and the Beck Depression Inventory-II (BDI-II) on patients and spouses. Thirty men and 15 women had a mean age of 71.5 years (range 53-85), average PD duration of 10 years (range 1-26), a mean "on" H&Y stage of 2.8 and an MMSE mean score of 26 (range 13-30). There was good correlation between the HAMD-17 and the BDI-II scores in both patients (r = 0.69, P = 0.001) and spouses (r = 0.66, P < 0.001). A moderate correlation was noted between the spouse HAMD-17 score and the patient UPDRS-motor score (r = 0.34; P = 0.02), the age of PD onset (r = 0.33; P = 0.02) and patient HAMD-17 scores (r= 0.29; P = 0.05). A stronger correlation was noted between spouse HAMD-17 scores and the years of PD duration (r= 0.43; P = 0.003). There was a significant difference in the mean spouse HAMD-17 scores among PD patients with sleep disturbances versus those who did not (10.2 vs. 6.4; P = 0.04). However, on stepwise regression analysis, only the duration of PD remained significant (adjusted r = 0.17; P = 0.003). No difference was noted with hallucinations, delusions or incontinence. We concluded that the duration of PD appears to be the strongest predictor of depressive symptoms among spouse-caregivers in this small cohort.     

Revision of Failed Gastric Bypass to Distal Roux-en-Y Gastric Bypass: A Review of 65 Cases

Background: No bariatric operation has been documented to effect adequate weight loss in all patients. Patients with inadequate weight loss or significant weight regain with an anatomically intact short-limb gastric bypass, of which the Fobi pouch operation (FPO) for obesity is a modification, are usually revised to a distal Roux-en-Y gastric bypass (DRYGBP) to enhance weight loss. Method: A retrospective review of the charts of all patients who had a revision to a DRYGBP at our Center during an 8-year period was carried out and the findings analyzed. Results: 65 patients who had the FPO had a revision to the DRYGBP.Most were super obese patients who, even though they had lost significant weight, were still morbidly obese. Some were patients who had not lost adequate weight or <40% excess weight, and a small number were patients who requested more weight loss even though they had a BMI of < 35. 15 patients developed protein malnutrition requiring supplemental feeding. 6 required rerevision to short-limb gastric bypass. Conclusion: Revision of short-limb gastric bypass to DRYGBP usually enhances weight loss but at a cost of an increased incidence of protein malnutrition.     

Remembering the color of objects: an ERP investigation of source memory

Subjects studied pictures of common objects outlined in either red or green and were asked to memorize the objects and their associated colors. Event-related potentials (ERPs) were recorded during subsequent inclusion (i.e. item) and exclusion (i.e. source) memory tasks. The main goal of the experiment was to determine if brain signatures for familiarity and recollection, two behavioral processes thought to account for episodic memory performance, would be observed in the pattern of ERP results. For correctly recognized items, early, posterior old/new effects were recorded (approximately 300--600 ms) that did not differ in magnitude or scalp distribution between item and source memory tasks. A subsequent long-duration occipitally focused negativity (approximately 800 ms peak) was evident in the source but not the item memory task. The ERPs associated with 'source errors' in the source memory task also showed robust early old/new effects. However, 'source error' ERPs lacked frontal scalp activity compared to those associated with correct source attribution. The data suggest that a recollective response may require frontal involvement whereas a decision based on familiarity may not.     

Exposure to environmental tobacco smoke: association with personal characteristics and self reported health conditions

STUDY OBJECTIVE: To examine the association between exposure to environmental tobacco smoke (ETS) and demographic, lifestyle, occupational characteristics and self reported health conditions. DESIGN: Cross sectional study, using data from multiphasic health checkups between 1979 and 1985. SETTING: Large health plan in Northern California, USA. PARTICIPANTS: 16 524 men aged 15-89 years and 26 197 women aged 15-105 years who never smoked. RESULTS: Sixty eight per cent of men and 64 per cent of women reported any current ETS exposure (at home, in small spaces other than home or in large indoor areas). The exposure time from all three sources of ETS exposure correlated negatively with age. Men and women reporting high level ETS exposure were more likely to be black and never married or separated/divorced, to have no college or partial college education, to consume three alcoholic drink/day or more and to report exposure to several occupational hazards. Consistent independent relations across sexes were found between any current exposure to ETS and a positive history of hay fever/asthma (odds ratio (OR)=1.22 in men, 1.14 in women), hearing loss (OR=1.30 in men, 1.27 in women), severe headache (OR=1.22 in men, 1.17 in women), and cold/flu symptoms (OR=1.52 in men, 1.57 in women). Any current ETS exposure was also associated with chronic cough (OR=1.22) in men and with heart disease (OR=1.10) in women. Self reported stroke was inversely associated with any current ETS exposure in men (OR=0.27). No associations were noted for cancer or tumour and for migraine. CONCLUSION: ETS exposure correlated with several personal characteristics potentially associated with adverse health outcomes. Although the study design precluded causal inference, ETS exposure was associated with several self reported acute and chronic medical conditions.