p53 protein or BID protein select the route to either apoptosis (programmed cell death) or to cell cycle arrest opposing carcinogenesis after DNA damage by ROS

p53 is a tumour-suppressor protein of human cells that prevents their entry into the route to carcinogenesis. Furthermore, p53 protein acts at the p53-response loci in genomic DNA to facilitate the switch-on of genes that can be expressed by the biosynthesis of routing-proteins for apoptosis or stalling of cellular proliferation (via cell cycle progression checkpoint arrests). Moreover, oxidative stress by reactive oxygen species (ROS) such as the hydroxyl radical (*OH) produced by ionizing radiation (carcinogenic) triggers p53 activation in response to the damage of DNA (followed by initiation of DNA-repair mechanisms). Phosphorylation of the BID protein may lead to the recovery from DNA-damage by ROS.     

Effects of fluorotelomer alcohol 8:2 FTOH on steroidogenesis in H295R cells: Targeting the cAMP signalling cascade

Previous studies have demonstrated that perfluorinated chemicals (PFCs) can affect reproduction by disruption of steroidogenesis in experimental animals. However, the underlying mechanism(s) of this disruption remain unknown. Here we investigated the effects and mechanisms of action of 1H, 1H, 2H, 2H-perfluoro-decan-1-ol (8:2 FTOH) on steroidogenesis using a human adrenocortical carcinoma cell line (H295R) as a model. H295R cells were exposed to 0, 7.4, 22.2 or 66.6 μM 8:2 FTOH for 24 h and productions of progesterone, 17α-OH-progesterone, androstenedione, testosterone, deoxycorticosterone, corticosterone and cortisol were quantified by HPLC-MS/MS. With the exception of progesterone, 8:2 FTOH treatment significantly decreased production of all hormones in the high dose group. Exposure to 8:2 FTOH significantly down-regulated cAMP-dependent mRNA expression and protein abundance of several key steroidogenic enzymes, including StAR, CYP11A, CYP11B1, CYP11B2, CYP17 and CYP21. Furthermore, a dose-dependent decrease of cellular cAMP levels was observed in H295R cells exposed to 8:2 FTOH. The observed responses are consistent with reduced cellular cAMP levels. Exposure to 8:2 FTOH resulted in significantly less basal (+ GTP) and isoproterenol-stimulated adenylate cyclase activities, but affected neither total cellular ATP level nor basal (−GTP) or NaF-stimulated adenylate cyclase activities, suggesting that inhibition of steroidogenesis may be due to an alteration in membrane properties. Metabolites of 8:2 FTOH were not detected by HPLC-MS/MS, suggesting that 8:2 FTOH was not metabolized by H295R cells. Overall, the results show that 8:2 FTOH may inhibit steroidogenesis by disrupting the cAMP signalling cascade.     

Malaria prevention in The Gambia: patterns of expenditure and determinants of demand at the household level

OBJECTIVE: To provide a better understanding of (1) the amounts households in The Gambia spend on a wide variety of malaria prevention measures, (2) how expenditure fluctuates throughout the year and (3) the main determinants of expenditure. METHODS: A random sample of 1700 households from the Farafenni region were interviewed about their expenditure on malaria prevention over the past 2 weeks. Interviews were staggered over 12 months. Expenditure was measured for bed nets, treating and repairing bed nets, aerosols, coils, indoor spraying, smoke and other prevention strategies such as drinking herbs and cleaning the outside environment. Results Expenditure on bed nets, including treatment and repair, constituted only 10% of total expenditure on malaria prevention. Every fortnight, households spent an average of 8.40 Dalasis (D) on coils, 4.20 D on indoor sprays, 3.09 D on smoke and 3.06 D on aerosols, together making up 81% of total fortnightly expenditure. Of the 442 households that did not own a bed net, 68% said it was because they could not afford one. Every 2 months, the same households spent an average of US 5 dollars, the equivalent to the cost of an insecticide treated bed net, on other forms of prevention. Total expenditure was 42% higher during the wet season than for the rest of the year. For every month of the year, coils were the dominant form of prevention expenditure. Wealth, age, occupation of household head, location of residence and month of the year were significant determinants of prevention expenditure. CONCLUSIONS: Households in The Gambia spend considerable amounts on a range of malaria prevention products and activities throughout the year. Bed nets represent a relatively small proportion of this expenditure even though they are perceived to be the most efficient and effective method of malaria control. A more concerted effort is needed to develop appropriate targeting strategies to encourage bed net use especially for children <5 years of age. Equal emphasis should be given to addressing barriers to purchasing nets such as their relative high upfront cost.     

Are infrared and thermistor thermometers interchangeable for measuring localized skin temperature?

Localized skin temperature must be measured by accurate and reliable thermometers to effectively evaluate treatment outcomes, monitor changes, and predict potential complications. This study compared localized skin temperature measurements with a contact thermistor thermometer used as a reference standard and a noncontact infrared (IR) skin thermometer to determine their interchangeability with calculated Bland-Altman limits of agreement. Fifty-five adults ages 50 to 89 participated in the study in which data were collected in a climate-controlled room over 3 measurement periods, 1 week apart. The thermistor and IR thermometers were interchangeable with a limit of agreement of +/- 1.5 degrees C. This limit of agreement is acceptable as a reference standard for IR thermometers to measure localized skin temperature in clinical settings.     

Down syndrome and the molecular pathogenesis resulting from trisomy of human chromosome 21

Chromosome copy number aberrations, anueploidies, are common in the human population but generally lethal. However, trisomy of human chromosome 21 is compatible with life and people born with this form of aneuploidy manifest the features of Down syndrome, named after Langdon Down who was a 19^th century British physician who first described a group of people with this disorder. Down syndrome includes learning and memory deficits in all cases, as well as many other features which vary in penetrance and expressivity in different people. While Down syndrome clearly has a genetic cause - the extra dose of genes on chromosome 21 - we do not know which genes are important for which aspects of the syndrome, which biochemical pathways are disrupted, or, generally how design therapies to ameliorate the effects of these disruptions. Recently, with new insights gained from studying mouse models of Down syndrome, specific genes and pathways are being shown to be involved in the pathogenesis of the disorder. This is opening the way for exciting new studies of potential therapeutics for aspects of Down syndrome, particularly the learning and memory deficits.     

Spinal motoneuron synaptic plasticity after axotomy in the absence of inducible nitric oxide synthase

Background

Astrocytes play a major role in preserving and restoring structural and physiological integrity following injury to the nervous system. After peripheral axotomy, reactive gliosis propagates within adjacent spinal segments, influenced by the local synthesis of nitric oxide (NO). The present work investigated the importance of inducible nitric oxide synthase (iNOS) activity in acute and late glial responses after injury and in major histocompatibility complex class I (MHC I) expression and synaptic plasticity of inputs to lesioned alpha motoneurons.

Methods

In vivo analyses were carried out using C57BL/6J-iNOS knockout (iNOS^-/-) and C57BL/6J mice. Glial response after axotomy, glial MHC I expression, and the effects of axotomy on synaptic contacts were measured using immunohistochemistry and transmission electron microscopy. For this purpose, 2-month-old animals were sacrificed and fixed one or two weeks after unilateral sciatic nerve transection, and spinal cord sections were incubated with antibodies against classical MHC I, GFAP (glial fibrillary acidic protein - an astroglial marker), Iba-1 (an ionized calcium binding adaptor protein and a microglial marker) or synaptophysin (a presynaptic terminal marker). Western blotting analysis of MHC I and nNOS expression one week after lesion were also performed. The data were analyzed using a two-tailed Student's t test for parametric data or a two-tailed Mann-Whitney U test for nonparametric data.

Results

A statistical difference was shown with respect to astrogliosis between strains at the different time points studied. Also, MHC I expression by iNOS^-/- microglial cells did not increase at one or two weeks after unilateral axotomy. There was a difference in synaptophysin expression reflecting synaptic elimination, in which iNOS^-/- mice displayed a decreased number of the inputs to alpha motoneurons, in comparison to that of C57BL/6J.

Conclusion

The findings herein indicate that iNOS isoform activity influences MHC I expression by microglial cells one and two weeks after axotomy. This finding was associated with differences in astrogliosis, number of presynaptic terminals and synaptic covering of alpha motoneurons after lesioning in the mutant mice.     

Working while receiving chemotherapy: a survey of patients' experiences and factors that influence these

The purpose of this study was to estimate the number of patients who continue to work when undergoing ambulatory chemotherapy and to identify personal or treatment-related factors that influence this. Patients undergoing final cycles of adjuvant chemotherapy for breast or colorectal cancer or first-line chemotherapy for lymphoma at two cancer treatment centres were approached to take part in a cross sectional survey (n= 55, RR 55%). Sixty-four per cent (n= 35) of respondents were working when cancer was diagnosed. Fifty-four per cent (n= 19) of respondents were working when chemotherapy began but as treatment progressed only 29% (n= 10) continued to work in any capacity. The most important influencing factor when making decisions about work was the need to concentrate on looking after oneself. Overall, respondents found their employers and colleagues supportive but there was some evidence they became less supportive as treatment progressed. While this was a small study it highlights the need for health care professionals to understand patient's needs and wishes in relation to work while undergoing chemotherapy by including this issue as part of routine assessment. Strategies to allow those who wish to continue to work during treatment should be put in place early to support this.     

A randomized comparison of group cognitive-behavioral therapy and group interpersonal psychotherapy for the treatment of overweight individuals with binge-eating disorder

BACKGROUND: Cognitive-behavioral therapy (CBT) has documented efficacy for the treatment of binge eating disorder (BED). Interpersonal psychotherapy (IPT) has been shown to reduce binge eating but its long-term impact and time course on other BED-related symptoms remain largely unknown. This study compares the effects of group CBT and group IPT across BED-related symptoms among overweight individuals with BED. METHODS: One hundred sixty-two overweight patients meeting DSM-IV criteria for BED were randomly assigned to 20 weekly sessions of either group CBT or group IPT. Assessments of binge eating and associated eating disorder psychopathology, general psychological functioning, and weight occurred before treatment, at posttreatment, and at 4-month intervals up to 12 months following treatment. RESULTS: Binge-eating recovery rates were equivalent for CBT and IPT at posttreatment (64 [79%] of 81 vs 59 [73%] of 81) and at 1-year follow-up (48 [59%] of 81 vs 50 [62%] of 81). Binge eating increased slightly through follow-up but remained significantly below pretreatment levels. Across treatments, patients had similar significant reductions in associated eating disorders and psychiatric symptoms and maintenance of gains through follow-up. Dietary restraint decreased more quickly in CBT but IPT had equivalent levels by later follow-ups. Patients' relative weight decreased significantly but only slightly, with the greatest reduction among patients sustaining recovery from binge eating from posttreatment to 1-year follow-up. CONCLUSIONS: Group IPT is a viable alternative to group CBT for the treatment of overweight patients with BED. Although lacking a nonspecific control condition limits conclusions about treatment specificity, both treatments showed initial and long-term efficacy for the core and related symptoms of BED.