Integrating genetic and clinical data to predict impulse control disorders in Parkinson's disease.

BACKGROUND AND PURPOSE: Impulse control disorders (ICDs) are frequent in Parkinson's disease (PD), with associated clinical and genetic risk factors. This study was aimed at analyzing the clinical features and the genetic background that underlie ICDs in PD. METHODS: We included 353 patients with PD in this study (58.9% men, mean age 62.4 ± 10.58 years, mean age at disease onset 52.71 ± 11.94 years). We used the validated Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease for ICDs screening. Motor, nonmotor, and treatment-related features were evaluated according to the presence of ICDs. Twenty-one variants related to dopaminergic, serotonergic, glutamatergic, and opioid neurotransmitter systems were assessed. Association studies between polymorphisms and ICDs were performed. The combination of clinical and genetic variables was analyzed with receiver operating characteristic curves to assess the predictability of experiencing ICDs. RESULTS: Impulse control disorders appeared in 25.1% of the cases. Patients with ICDs were younger and presented a higher rate of anxiety. Treatment with dopamine agonists increased the risk of ICDs and it was dose dependent (P < 0.05). Genetic association studies showed that the DOPA decarboxylase gene (DDC), rs1451375, might modulate the risk of ICDs. Plotting the clinical-genetic model, the predictability of ICDs increased 11% (area under curve = 0.80; z = 3.22, P = 0.001) when adding the genotype data for single nucleotide polymorphisms. CONCLUSIONS: Polymorphisms in DDC might act as risk markers for ICDs in PD. The predictability of experiencing ICDs increased by adding genetic factors to clinical features. It is therefore important to assess the patient's genetic background to identify individuals at risk for ICDs.

Ambient particulate matter burden of disease in the Kingdom of Saudi Arabia.

BACKGROUND: Air pollution is one of the top 10 global health risk factors and has been associated with premature mortality, cardiovascular, cerebrovascular, respiratory, and metabolic disease. Currently, there is a lack of health assessments on the public health impacts of air pollution in the Kingdom of Saudi Arabia. AIM: This study aims to assess the ambient particulate matter burden of disease in the Kingdom of Saudi Arabia. METHODS: A comparative risk assessment (CRA) using the 2017 Global Burden of Disease was performed to estimate ambient particulate matter exposure, mortality, and lost years of a healthy life. Saudi Arabia population-weighted mean concentrations of particle mass with an aerodynamic diameter less than 2·5 µm (PM2.5), at an approximate 11 km × 11 km resolution was estimated using satellite-based estimates, chemical transport models, and ground-level measurements. The CRA for PM2.5 was based on relative risks originated from epidemiological studies using integrated exposure-response functions for ischemic heart disease, cerebrovascular disease, chronic obstructive pulmonary disease, lung cancer, lower respiratory infections, and type 2 diabetes. Mortality, years of life lost (YLL), years lived with disability (YLD) and disability-adjusted life years (DALYs) attributable to PM2.5 were estimated at the national level for all ages and both sexes from 1990 to 2017. RESULTS: In 2017, the annual exposure to ambient particulate matter in the population-weighted mean PM2.5 in Saudi Arabia was 87.9 µg/m3 (95% UI 29.6-197.9). The PM2.5 population-weighted mean has increased by 24% since 1990. Annual deaths attributable to PM2.5 were estimated at 8536 (95% UI 6046-11,080), representing 9% of the total annual deaths in Saudi Arabia. In 2017, 315,200 (95% UI 231,608-401,926) DALYs were attributable to PM2.5. Males contributed to 67% (209,822 (95% UI 151,322-277,503)) of DALYs, and females contributed to 33% (105,378 (95% UI 76,014-135,269) of DALYs. Ischemic heart disease represented 44% of the PM2.5 attributable DALYs, followed by type 2 diabetes (20%), lower respiratory infections (13%), stroke (11%), COPD (10%), and tracheal, bronchus, and lung cancer (3%). In 2017, 240,966 (95% UI 168,833-319,178) years of life lost (YLL) and 74,234 (95% UI 50,229-100,410) years lived with disability (YLD) were attributed to PM2.5. CONCLUSION: Ambient particulate matter is the fifth health risk factor in Saudi Arabia, contributing 9% of total mortality. Over the past 27 years, estimated exposure levels of PM2.5 in Saudi Arabia have been above WHO's air quality guidelines. Although since 2011 mortality and DALY rates attributable to PM2.5 have decreased, air pollution concentrations continue to increase. National and local authorities in Saudi Arabia should consider policies to reduce industrial and traffic-related air pollution in combination with the strengthening of current investments and improvements in health care and prevention services.

Health equity and burden of childhood asthma - related to air pollution in Barcelona.

BACKGROUND: Air pollution is one of the major health risk factors in urban populations. Air pollution has been associated with asthma in children. Air pollution has also been suggested to be distributed unequally within the cities, something that can lead to urban health inequalities. AIM: We aimed to estimate the number of childhood asthma cases attributable to three main air pollutants; Nitrogen dioxide (NO2), Particulate Matter (PM 2.5), and Black Carbon (BC) in the city of Barcelona, Spain. We also aimed to describe the distribution of those impacts depending on the social deprivation index in Barcelona. METHODS: We estimated the number of childhood asthma cases in Barcelona by applying a quantitative Health Impact Assessment (HIA) approach. Air pollution (NO2, PM2.5, and BC) exposure assessment was estimated using a land-use regression model. Two scenarios were assessed and compared the current levels of air pollution with 1) achieving the World Health Organization (WHO) guideline on exposure levels for NO2 and PM2.5 (scenario 1); and 2) achieving the minimum reported levels in a previously published meta-analysis (scenario 2), from where we also obtained the exposure-response functions. The relative risk and population attributable fraction (PAF) for each scenario and pollutant were estimated. Using the asthma incidence rate in Spain the expected number of asthma cases in Barcelona attributable to NO2, PM2.5, and BC for each scenario was estimated. RESULTS: The annual average levels of NO2, PM2.5, and BC at census levels were 56 µg/m3, 17.11 µg/m3, and 2.88 µg/m3, respectively. The number of asthma cases attributable to NO2 and PM2.5 (percentage of total cases) estimated in scenario 1 was 454 (18%) and 478 (19%) respectively. For scenario 2, the estimated number of cases attributable to NO2, PM2.5, and BC were 1230 (48%), 992 (39%) and 789 (31%) respectively. Although NO2 and BC showed differences between asthma cases and areas with different deprivation index, only BC differences were statistically significant between less and more deprived areas. CONCLUSIONS: This study estimated that up to 1230 (48%) of asthma cases in Barcelona could be attributable to air pollution each year. This study also found that in Barcelona, less socially deprived groups could be more affected by asthma-related to air pollution than those more socially deprived.

Detailed characterization of MLH1 p.D41H and p.N710D variants coexisting in a Lynch syndrome family with conserved MLH1 expression tumors.

Lynch syndrome (LS) is an autosomal dominant cancer-susceptibility disease caused by inactivating germline mutations in mismatch repair (MMR) genes. Variants of unknown significance (VUS) are often detected in mutational analysis of MMR genes. Here we describe a large family fulfilling Amsterdam I criteria carrying two rare VUS in the MLH1 gene: c.121G > C (p.D41H) and c.2128A > G (p.N710D). Collection of clinico-pathological data, multifactorial analysis, in silico predictions, and functional analyses were used to elucidate the clinical significance of the identified MLH1 VUS. Only the c.121G > C variant cosegregated with LS-associated tumors in the family. Diagnosed colorectal tumors were microsatellite unstable although immunohistochemical staining revealed no loss of MMR proteins expression. Multifactorial likelihood analysis classified c.2128A > G as a non-pathogenic variant and c.121G > C as pathogenic. In vitro functional tests revealed impaired MMR activity and diminished expression of c.121G > C. Accordingly, the N710 residue is located in the unconserved MLH1 C-terminal domain, whereas D41 is highly conserved and located in the ATPase domain. The obtained results will enable adequate genetic counseling of c.121G > C and c.2128A > G variant carriers and their families. Furthermore, they exemplify how cumulative data and comprehensive analyses are mandatory to refine the classification of MMR variants.

Environmental and health benefits from designating the Marmara Sea and the Turkish Straits as an emission control area (ECA).

Ship emissions degrade air quality and affect human health, and are increasingly becoming a matter of concern. Sulfur emission control areas (ECA), specific coastal regions where only low-sulfur fuels may be consumed by ocean-going ships, have proven to be useful tools to reduce ship-sourced air pollution along the North American, Canadian, and European North and Baltic Sea coastlines. The present work assesses the environmental and health benefits which would derive from designating an ECA in the Marmara Sea and the Turkish Straits (50 000 ships/year; 23 million inhabitants). Results show evidence that implementing an ECA would be technically viable and that it would reduce ship-sourced PM10 and PM2.5 ambient concentrations in Istanbul by 67%, and SO2 by 90%. The reduction of the air pollution burden on health was quantified as 210 hospital admissions from exposure to PM10, 290 hospital admissions from exposure to SO2, and up to 30 premature deaths annually due to ECA emission controls. Consequently, the designation of an ECA in the Marmara Sea and the Turkish Straits is evaluated as a positive, technically viable and real-world measure to reduce air pollution from ships in Turkey.

Identification of a founder EPCAM deletion in Spanish Lynch syndrome families.

Germline deletions at the 3'-end of EPCAM have been involved in the etiology of Lynch syndrome (LS). The aim of this study was to characterize at the molecular level Spanish families harboring EPCAM deletions. Non-commercial multiplex ligation-dependent probe amplification (MLPA) probes and long-range polymerase chain reaction (PCR) amplification were used to characterize each deletion. Haplotyping was performed by analyzing eight microsatellite markers and five MSH2single nucleotide polymorphisms (SNPs). Methylation of MSH2 was analyzed by methylation specific-MLPA. Tumors diagnosed in seven Spanish families harboring EPCAM deletions were almost exclusively colorectal. Mosaicism in MSH2 methylation was observed in EPCAM deletion carrier samples, being average methylation levels higher in normal colon and colorectal tumors (27.6% and 31.1%), than in lymphocytes and oral mucosa (1.1% and 0.7%). Three families shared the deletion c.858 + 2568_*4596del, with a common haplotype comprising 9.9 Mb. In two families the novel EPCAM deletion c.858 + 2488_*7469del was identified. This study provides knowledge on the clinical and molecular characteristics of mosaic MSH2 epimutations. The identification of an EPCAM founder mutation has useful implications for the molecular diagnosis of LS in Spain.

Health impact assessment of increasing public transport and cycling use in Barcelona: a morbidity and burden of disease approach.

OBJECTIVE: Quantify the health impacts on morbidity of reduced car trips and increased public transport and cycling trips. METHODS: A health impact assessment study of morbidity outcomes related to replacing car trips in Barcelona metropolitan (3,231,458 inhabitants). Through 8 different transport scenarios, the number of cases of disease or injuries related to physical activity, particulate matter air pollution <2.5 µm (PM2.5) and traffic incidents in travelers was estimated. We also estimate PM2.5 exposure and cases of disease in the general population. RESULTS: A 40% reduction in long-duration car trips substituted by public transport and cycling trips resulted in annual reductions of 127 cases of diabetes, 44 of cardiovascular diseases, 30 of dementia, 16 minor injuries, 0.14 major injuries, 11 of breast cancer and 3 of colon-cancer, amounting to a total reduction of 302 Disability Adjusted Life Years per year in travelers. The reduction in PM2.5 exposure in the general population resulted in annual reductions of 7 cases of low birth weight, 6 of preterm birth, 1 of cardiovascular disease and 1 of lower respiratory tract infection. CONCLUSIONS: Transport policies to reduce car trips could produce important health benefits in terms of reduced morbidity, particularly for those who take up active transportation.

Laser-induced periodic surface structures nanofabricated on poly(trimethylene terephthalate) spin-coated films.

Here we present a precise morphological description of laser-induced periodic surface structures (LIPSS) nanofabricated on spin-coated poly(trimethylene terephthalate) (PTT) films by irradiation with 266 nm, 6 ns laser pulses and by using a broad range of fluences and number of pulses. By accomplishing real and reciprocal space measurements by means of atomic force microscopy and grazing incidence wide- and small-angle X-ray scattering respectively on LIPSS samples, the range of optimum structural order has been established. For a given fluence, an increase in the number of pulses tends to improve LIPSS in PTT. However, as the pulse doses increase above a certain limit, a distortion of the structures is observed and a droplet-like morphology appears. It is proposed that this effect could be related to a plausible decrease of the molecular weight of PTT due to laser-induced chain photo-oxidation by irradiation with a high number of pulses. A concurrent decrease in viscosity enables destabilization of LIPSS by the formation of droplets in a process similar to surface-limited dewetting.

A dot-ELISA using a partially purified cathepsin-L-like protein fraction from Taenia solium cysticerci, for the diagnosis of human neurocysticercosis.

Human neurocysticercosis (NCC), caused by the cestode Taenia solium, is responsible for a significant amount of neurological morbidity and epilepsy in developing countries. The disease remains highly endemic in many areas, despite several efforts and interventions to control it. A simple, cheap and fast diagnostic assay that is suitable for use in field conditions is highly desired. In immunodiagnostics based on western immunoblots or standard ELISA, a cathepsin-L-like protein purified from the cysticercus fluid has previously performed well as an antigen. In a recent study in Peru, the same 53/25-kDa antigen was therefore used in the development of a dot-ELISA that could be employed for mass screenings under field conditions. The assay was standardized and tested not only against sera from a large group of NCC cases but also against sera from patients with other common parasitic infections, so that sensitivity and specificity could be assessed. For NCC, the assay gave better sensitivity in the detection of individuals with extraparenchymal cysts (94·4%-100%) or multiple parenchymal cysts (74·6%-80·0%) than in the detection of individuals with single parenchymal cysts (29·4%-45·1%). The assay also showed a high specificity for NCC (99·0%-100%), with a very low level of cross-reactivity with other parasitic infections. The dot-ELISA developed in this study is a highly specific, simple, cheap and rapid test for NCC that could be used under field conditions, even in the low-resource settings that are common in developing countries.

Data for a city-level health impact assessment of urban transport in Mauritius.

Participatory quantitative Health Impact Assessments (HIAs) in developing countries are rare partly due to data scarcity. This paper reports on primary data collected in the city of Port Louis to complete a HIA of urban transport planning in Mauritius. We conducted a full-chain participatory HIA to assess health impacts on the basis of a transport mode shift in Port Louis, Mauritius [1]. By applying mixed-methods, we estimated averted deaths per year and economic outcomes by assessing the health determinants of air pollution, traffic deaths and physical activity. The participatory quantitative HIA included [1] baseline data collection [2] co-validation of transport policy scenarios with stakeholders and [3] quantitative modelling of health impacts. We used the risk assessment method for HIA appraisal. The data can be reused for epidemiological analysis and different types of impact assessments.

Structure and morphology of thin films of linear aliphatic polyesters prepared by spin-coating.

Thin films, with thicknesses from 10 to 400 nm of linear aliphatic polyesters (X, Y), based on propylenediol (X = 3) and on dicarboxylic acid of different chain length (Y = 2, 3, and 4 CH(2) units) were prepared by spin coating of CHCl(3) polymer solutions with different polymer concentrations. Morphology and structure of the spin coated thin films were investigated by atomic force microscopy (AFM) and by grazing incidence X-ray scattering techniques at small, (GISAXS) and wide angles (GIWAXS). AFM revealed a strong dewetting for all three polymers for coatings thinner than 100 nm. The polymer films are clearly semicrystalline for thicknesses higher than 50 nm. GIWAXS of the thicker films revealed their oriented crystalline nature. An edge-on-lamellae morphology is clearly shown by the AFM-phase images even for relatively thin films. SAXS with the beam parallel to the sample plane also support the presence of lamellae perpendicular to the substrate. The use of a mu-beam helped to interpret the GIWAXS patterns and allowed to obtain oriented WAXS patterns from melt solidified filaments. Thus, a crystal chain packing is proposed for the three polymers and consequently the indexing of the observed reflections. Accordingly, the polymer chains lie parallel to the substrate being the bc plane of the monoclinic crystal unit cell parallel to the substrate.

Flat-on lamellae in spin-coated, stable films of poly(propylene azelate).

Thin films (5-500 nm thick) of the linear aliphatic polyester (3,7) poly(propylene azelate) (PPAz) were prepared by spin-coating of CHCl(3) polymer solutions with different polymer concentrations. The morphology and structure of the spin-coated thin films were investigated by atomic force microscopy (AFM) and by grazing incidence wide-angle X-ray scattering (GIWAXS) techniques. AFM revealed the continuous nature of the flat, spherulitic films which are stable against dewetting even for polymer coatings as thin as 15 nm. GIWAXS patterns revealed a high crystal orientation of the films. A sharp reflection on the meridian whose spacing is related to the polymer chain unit length (c-axis) supports the presence of flat-on lamellae morphology in the whole range of film thicknesses investigated. The flat-on lamellae morphology is also supported by AFM images. A triclinic unit cell with the c*-axis perpendicular to the substrate is proposed for PPAz. The repulsion of the long aliphatic spacer by the Si-substrate is invoked as the main reason for the flat-on morphology observed.

Argentinian/Chilean validation of the Spanish-language version of Addenbrooke's Cognitive Examination III for diagnosing dementia. / Validación argentino-chilena de la versión en español del test Addenbrooke's Cognitive Examination III para el diagnóstico de demencia.

BACKGROUND: The Addenbrooke's Cognitive Examination III (ACE-III), an adaptation of the ACE cognitive screening test, has been demonstrated to have high sensitivity and specificity in detecting cognitive impairment in patients with dementia and other neurological and psychiatric disorders. Although the Spanish-language version of the ACE-III has already been validated in Spain, it is yet to be validated in Latin America. The aim of this study was to validate the ACE-III test in an Argentinean and Chilean population. METHODS: ACE-III was administered to 70 patients with Alzheimer disease, 31 patients with behavioural variant frontotemporal dementia, and a control group of 139 healthy volunteers. Participants were recruited at centres in both countries. RESULTS: The Spanish-language version of ACE-III was found to have good internal consistency (Cronbach's alpha=0.87). We found significant differences in total ACE-III scores between patients with Alzheimer disease and controls (p< .05) and between patients with Alzheimer disease and bvFTD (p< .05). With a cut-off point of 86, 98.6% of AD patients, 83.9% of behavioural variant frontotemporal dementia patients, and 84.2% of controls were correctly classified. CONCLUSIONS: This study shows that the Spanish-language version of ACE-III continues to be an effective tool for detecting cognitive dysfunction in patients with dementia.

Participatory quantitative health impact assessment of urban transport planning: A case study from Eastern Africa.

BACKGROUND: High rates of motorization in urban areas of Africa have adverse effects on public health. Transport-related mortality will increase as a result of inadequate transport infrastructure, air pollution and sedentary lifestyles. Health Impact Assessments (HIAs) have proven to be a successful tool to predict and mitigate negative health impact of urban transport planning policies, programmes or projects. Yet, there is a gap of evidence on transport and health in African countries. The aim of this study is assessing the health impacts of transport scenarios in Port Louis (city of 119,018 inhabitants in Mauritius) using a full chain participatory HIA model. METHODS: We estimated health and economic impacts associated to transport scenarios with qualitative data and quantitative comparative risk assessment methods. The health impact modeling was based on differences between the baseline and three transport scenarios (worse, good, ideal), estimating the averted deaths per year and economic outcomes by assessing health determinants of air pollution (AP), traffic deaths and physical activity (PA). Data on air pollution and traffic fatalities were obtained from public data sources. Data used to construct scenarios, establish baseline travel mode shares and physical activity were collected through (a) open-ended individual interviews (IDIs) with 14 stakeholders (b) closed-ended survey questions to 600 citizens and (c) 2 focus group discussions (FGDs) with the same 14 stakeholders from (a). RESULTS: In Port Louis, the worse-case transport scenario (doubling in car trips and a reduction in walking, motorcycle, and public transport), resulted in a total increment of 3.28 premature deaths per year. The good-case scenario (reducing car trips by half and increasing walking, motorcycle, and public transport trips) resulted in a total increment of 0.79 premature deaths per year. The ideal-case scenario (reduction in car and motorcycle trips and an increase in walking and public transport trips) resulted in a total reduction of 13.72 premature deaths per year. We estimated USD 23 millions of economic benefits related to mortality if the ideal-case was achieved. CONCLUSION: Participatory HIA shows that implementing transport policies aiming for less than an ideal situation may not be adequate or sufficient to avoid negative transport-related mortality in Mauritius. Urban transport planning is an opportunity to encourage physical activity in rapidly urbanizing settings of Africa. Transport policies should aim to restrict all forms of private motorized vehicles and promote active and public transport to support public health. We highly recommend the use of participatory approaches in quantitative HIA to ensure context specificity and policy relevance.

Health impacts of bike sharing systems in Europe.

BACKGROUND: Bike-sharing systems (BSS) have been implemented in several cities around the world as policies to mitigate climate change, reduce traffic congestion, and promote physical activity. This study aims to assess the health impacts (risks and benefits) of major BSS in Europe. METHODS: We performed a health impact assessment study to quantify the health risks and benefits of car trips substitution by bikes trips (regular-bikes and/or electric-bikes) from European BSS with >2000 bikes. Four scenarios were created to estimate the annual expected number of deaths (increasing or reduced) due to physical activity, road traffic fatalities, and air pollution. A quantitative model was built using data from transport and health surveys and environmental and traffic safety records. The study population was BSS users between 18 and 64 years old. RESULTS: Twelve BSS were included in the analysis. In all scenarios and cities, the health benefits of physical activity outweighed the health risk of traffic fatalities and air pollution. It was estimated that 5.17 (95%CI: 3.11-7.01) annual deaths are avoided in the twelve BSS, with the actual level of car trip substitution, corresponding to an annual saving of 18 million of Euros. If all BSS trips replaced car trips, 73.25 deaths could be avoided each year (225 million Euros saving) in the twelve cities. CONCLUSIONS: The twelve major Bike-sharing systems in Europe provide health and economic benefits. The promotion of shifting car drivers to use BSS can significantly increase the health benefits. BSS in Europe can be used as a tool for health promotion and prevention.

Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor.

The development of new therapeutic strategies is essential for the management of gliomas, one of the most malignant forms of cancer. We have shown previously that the growth of the rat glioma C6 cell line is inhibited by psychoactive cannabinoids (I. Galve-Roperh et al., Nat. Med., 6: 313-319, 2000). These compounds act on the brain and some other organs through the widely expressed CB(1) receptor. By contrast, the other cannabinoid receptor subtype, the CB(2) receptor, shows a much more restricted distribution and is absent from normal brain. Here we show that local administration of the selective CB(2) agonist JWH-133 at 50 microg/day to Rag-2(-/-) mice induced a considerable regression of malignant tumors generated by inoculation of C6 glioma cells. The selective involvement of the CB(2) receptor in this action was evidenced by: (a) the prevention by the CB(2) antagonist SR144528 but not the CB(1) antagonist SR141716; (b) the down-regulation of the CB(2) receptor but not the CB(1) receptor in the tumors; and (c) the absence of typical CB(1)-mediated psychotropic side effects. Cannabinoid receptor expression was subsequently examined in biopsies from human astrocytomas. A full 70% (26 of 37) of the human astrocytomas analyzed expressed significant levels of cannabinoid receptors. Of interest, the extent of CB(2) receptor expression was directly related with tumor malignancy. In addition, the growth of grade IV human astrocytoma cells in Rag-2(-/-) mice was completely blocked by JWH-133 administration at 50 microg/day. Experiments carried out with C6 glioma cells in culture evidenced the internalization of the CB(2) but not the CB(1) receptor upon JWH-133 challenge and showed that selective activation of the CB(2) receptor signaled apoptosis via enhanced ceramide synthesis de novo. These results support a therapeutic approach for the treatment of malignant gliomas devoid of psychotropic side effects.

[Pyomyositis of hip obturator muscles]. / Piomiositis de los obturadores de la cadera.

Obturator internus muscle abscess (pyomyositis) is extremely rare in temperate environments, although there has been a recent reported increase in prevalence. There usually is a delay in diagnosis and onset of treatment. In addition to our case, we reviewed all cases of pyomyositis of hip muscles found in a review of the recent medical literature.

Ultrasound control of magnet growing rod distraction in early onset scoliosis. / Control ecográfico en la distracción de los tallos de crecimiento magnéticos en la escoliosis de aparición precoz.

The growing rod technique is currently one of the most common procedures used in the management of early onset scoliosis. However, in order to preserve spine growth and control the deformity it requires frequent surgeries to distract the rods. Magnetically driven growing rods have recently been introduced with same treatment goal, but without the inconvenience of repeated surgical distractions. One of the limitations of this technical advance is an increase in radiation exposure due to the increase in distraction frequency compared to conventional growing rods. An improvement of the original technique is presented, proposing a solution to the inconvenience of multiple radiation exposure using ultrasound technology to control the distraction process of magnetically driven growing rods.

Genome-wide linkage analysis and tumoral characterization reveal heterogeneity in familial colorectal cancer type X.

BACKGROUND: Familial colorectal cancer type X (FCCTX) fulfils clinical criteria defining Lynch syndrome (LS), but is not related to germline mutations in DNA mismatch-repair genes. Its aetiology remains unexplained and there is little evidence of involvement of the common colorectal carcinogenetic pathways. We aimed to identify susceptibility loci and gain insights into carcinogenic pathways involved FCCTX tumour development. METHODS: We performed a linkage analysis in 22 FCCTX families. We also constructed a tissue microarray in order to define an immunohistochemical (IHC) profile for FCCTX tumours (N = 27) by comparing them to three other types of colorectal tumors: LS (N = 18), stable early-onset (N = 31) and other sporadic disease (N = 80). Additionally, we screened for BRAF/KRAS mutations and determined CpG island methylator phenotype (CIMP) status for all FCCTX tumours. RESULTS: We found suggestive evidence of linkage at four chromosomal regions; 2p24.3, 4q13.1, 4q31.21 and 12q21.2-q21.31. We screened genes in 12q21 and ruled out the implication of RASSF9 and NTS, good candidates due to their potential involvement in carcinogenesis and colorectal epithelium development. Based on IHC profiles FCCTX tumours did not form a single, exclusive cluster. They were clearly different from LS, but very similar to stable early onset tumours. The CIMP and chromosomal instability pathways were implicated in one-third and one-quarter of FCCTX cases, respectively. The remaining cases did not have alterations in any known carcinogenic pathways. CONCLUSIONS: Our results highlight the heterogeneity of FCCTX tumours and call into question the utility of using only clinical criteria to identify FCCTX cases.

Involvement of the cAMP/protein kinase A pathway and of mitogen-activated protein kinase in the anti-proliferative effects of anandamide in human breast cancer cells.

Anandamide (ANA) inhibits prolactin- and nerve growth factor (NGF)-induced proliferation of human breast cancer cells by decreasing the levels of the 100 kDa prolactin receptor (PRLr) and the high affinity trk NGF receptor, respectively, and by acting via CB(1)-like cannabinoid receptors. However, the intracellular signals that mediate these effects are not known. Here, we show that, in MCF-7 cells: (i) forskolin and the mitogen-activated protein kinase (MAPK) kinase inhibitor PD098059 prevent, and the protein kinase A inhibitor RpcAMPs mimics, the inhibitory effects of ANA on cell proliferation and PRLr/trk expression and (ii) ANA inhibits forskolin-induced cAMP formation and stimulates Raf-1 translocation and MAPK activity, in a fashion sensitive to the selective CB(1) antagonist SR141716A. ANA stimulation of MAPK was enhanced by inhibitors of ANA hydrolysis. Forskolin inhibited MAPK and ANA-induced Raf-1 translocation. These findings indicate that, in MCF-7 cells, ANA inhibits adenylyl cyclase and activates MAPK, thereby exerting a down-regulation on PRLr and trk levels and a suppression of cell proliferation.