Anxiety and depression in Nepal: prevalence, comorbidity and associations

BACKGROUND: Anxiety and depression are two important contributors to the global burden of disease. In many developing countries, including Nepal, their prevalences are yet to be assessed. METHODS: A nationwide cross-sectional study was conducted among a representative sample of Nepalese adults aged 18–65 years (N = 2100), selected by multistage random cluster sampling and interviewed at home during unannounced visits. The validated questionnaires included the Hospital Anxiety and Depression Scale (HADS), to detect cases of anxiety (HADS-A), depression (HADS-D) and comorbid anxiety and depression (HADS-cAD), the Eysenck Personality Questionnaire Revised Short Form-Neuroticism (EPQRS-N), and the World Health Organization Quality of Life 8-question scale (WHOQOL-8). Logistic regression analyses were used to explore associations of caseness with four groups of variables: demographic, domicile, substance use, and behavioural and health. RESULTS: Age- and gender-adjusted point prevalences of HADS-A, HADS-D and HADS-cAD were 16.1, 4.2 and 5.9 % respectively. In a multivariate model, HADS-A was positively associated with urban residence (AOR = 1.82; p < 0.001) and neuroticism (AOR = 1.32; p < 0.001), and negatively with alcohol consumption (AOR = 0.71; p = 0.041). HADS-D was positively associated with marijuana use (AOR = 3.61; p = 0.017) and negatively with quality of life (QoL) (AOR = 0.86; p < 0.001). HADS-cAD was positively associated with widowhood (AOR = 2.71; p = 0.002), urban residence (AOR = 2.37; p = 0.001), living at altitude ≥2000 m (AOR = 2.32; p = 0.002) and neuroticism (AOR = 1.26; p < 0.001), and negatively with alcohol use (AOR = 0.56; p = 0.026) and QoL (AOR = 0.79; p < 0.001). CONCLUSION: Depression and anxiety are important mental health conditions in Nepal, and major contributors to public ill health, being very highly prevalent, comorbid and associated with psychosocial burden. They are also linked to the unique topography, habitation and social structure of the country. High prevalence coupled with the disabling nature of these disorders establishes their health-care priority and their importance in national health policy

Comorbidities of psychiatric and headache disorders in Nepal: implications from a nationwide population-based study

Background Headache disorders, anxiety and depression – the major disorders of the brain – are highly comorbid in the western world. Whether this is so in South Asia has not been investigated, but the question is of public-health importance to countries in the region. We aimed to investigate associations, and their direction(s), between headache disorders (migraine, tension-type headache [TTH] and headache on ≥15 days/month) and psychiatric manifestations (anxiety, depression and neuroticism), and how these might affect quality of life (QoL). Methods In a nationwide, cross-sectional survey of the adult Nepalese population (N = 2100), trained interviewers applied: 1) a culturally-adapted version of the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation (HARDSHIP) questionnaire to diagnose headache disorders; 2) a validated Nepali version of the Hospital Anxiety and Depression Scale (HADS) to detect anxiety (HADS-A), depression (HADS-D) and comorbid anxiety and depression (HADS-cAD); 3) a validated Nepali version of the Eysenck Personality Questionnaire Revised Short Form-Neuroticism (EPQRS-N); and 4) the World Health Organization Quality of Life 8-question scale (WHOQOL-8). Associations with headache types were analysed using logistic regression for psychiatric caseness and linear regression for neuroticism. Adjustments were made for age, gender, household consumption, habitat, altitude and use of alcohol and marijuana. Results HADS-A was associated with any headache (p = 0.024), most strongly headache on ≥15 days/month (AOR = 3.2) followed by migraine (AOR = 1.7). HADS-cAD was also associated with any headache (p = 0.050, more strongly among females than males [p = 0.047]) and again most strongly with headache on ≥15 days/month (AOR = 2.7), then migraine (AOR = 2.3). Likewise, neuroticism was associated with any headache (p < 0.001), most strongly with headache on ≥15 days/month (B = 1.6), followed by migraine (B = 1.3). No associations were found between HADS-D and any headache type, or between TTH and any psychiatric manifestation. Psychiatric caseness of any sort, when comorbid with migraine or TTH, aggravated the negative impact on QoL (p < 0.001). Conclusion Headache disorders are highly comorbid with anxiety and show associations with neuroticism in Nepal, with negative consequences for QoL. These findings call for reciprocal awareness, and a holistic coordinated approach to management and in the health service. Care for common headache and common psychiatric disorders should be integrated in primary care.publishedVersion© 2016 Risal et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/

New Radiocarbon Ages on Percussion-Fractured and Flaked Proboscidean Limb Bones from Yukon, Canada

Proboscidean limb bones discovered in Yukon during the 1960s and 1970s exhibit fracture patterns, notches, and bone flakes that are characteristic of percussion. Because of the unique properties of thick cortical proboscidean bone (probably woolly mammoth Mammuthus primigenius or less likely American mastodon Mammut americanum), some researchers hypothesized that these fracture patterns represent intentional hammerstone modification by humans for marrow extraction and bone tool production. As such, these fracture patterns represent evidence of early human dispersal into Eastern Beringia. Radiocarbon dating in the late 1980s indicated that the bone breakage occurred between about 25 000 and 40 000 radiocarbon years before present (14C yr BP). We report 11 new radiocarbon ages using ultra-filtration methods on a different sample of similarly fractured and flaked bones from Yukon. Only two of the radiocarbon ages fall within the expected range of 25 000 to 40 000 14C yr BP. Six other ages are non-finite, with five being more than 49 100 14C yr BP. Three finite ages range between 46 500 and 50 500 14C yr BP with large standard deviations, and these ages may also be non-finite. Two testable hypotheses to explain the observed breakage patterns were developed, the first being that humans broke the bones and the second that some presently unknown geological process broke the bones. Further research is needed to test these two hypotheses.Des ossements de membres de proboscidiens découverts au Yukon dans les années 1960 et 1970 présentent des structures de fractures, des encoches et des traces d’enlèvements d’éclats caractéristiques de la percussion. En raison des propriétés uniques de l’os cortical proboscidien (provenant probablement d’un mammouth laineux Mammuthus primigenius ou, ce qui est moins probable, d’un mastodonte américain Mammut americanum), certains chercheurs ont avancé une hypothèse selon laquelle ces structures représentent des modifications intentionnelles faites au marteau en pierre par des humains, à des fins d’extraction de la moelle et de production d’outils en os. En tant que telles, ces structures de fractures témoignent de la présence ancienne d’humains dans l’est de la Béringie. Vers la fin des années 1980, la datation au radiocarbone a permis de déterminer que les fractures auraient été faites il y a environ 25 000 à 40 000 années radiocarbones avant le présent (14C ans BP). Nous faisons état de 11 nouveaux âges au radiocarbone établis au moyen de méthodes d’ultrafiltration sur un échantillon différent d’os provenant également du Yukon et présentant de semblables fractures et traces d’enlèvements d’éclats. Seulement deux des âges au radiocarbone font partie de la gamme attendue variant entre 25 000 et 40 000 14C ans BP. Six autres âges sont non finis, dont cinq ayant plus de 49 100 14C ans BP. Trois âges finis varient entre 46 500 et 50 500 14C ans BP et ont d’importants écarts-types, et ces âges pourraient également être non finis. Deux hypothèses testables ont été émises afin d’expliquer les structures de fractures observées, la première étant que les fractures ont été causées par des humains et la seconde étant que les fractures sont le résultat d’un processus géologique inconnu à ce jour. Des recherches plus approfondies s’imposent afin de mettre ces deux hypothèses à l’épreuve

Characterization of an Atlantic cod (Gadus morhua) embryonic stem cell cDNA library

<p>Abstract</p> <p>Background</p> <p>The Atlantic cod is an ecologically and economically important North Atlantic fish species and also an emerging aquaculture species. To study gene expression in Atlantic cod embryonic stem (ES) cells, our goal was to generate and analyze expressed sequence tags (ESTs) from an ES cell cDNA library of mRNA consisting of approximately 3,900 ESTs.</p> <p>Results</p> <p>We sequenced 3,935 EST clones using a directional cDNA library made from pooled ES cells harvested at the blastula stage. Quality filtering of these ESTs allowed identification of 2,719 high-quality sequences with an average length of 442 bp containing 368 contigs and 1,276 singletons (1,644 unique sequences). BLASTX searches produced 889 significant (E-value < 10^-3) hits, of which 698 (42.5%) were annotated with Gene Ontology terms (E-value < 10^-6). The number of unknown unique sequences was 946 (57.5%). All the high-quality EST sequences have been deposited in GenBank (GenBank: 2,719 sequences in UniGene library dbEST id: 22,021). Gene discovery and annotations are presented and discussed.</p> <p>Conclusion</p> <p>This set of ESTs represents one of the first attempts to describe mRNA in ES cells from a marine cold-water fish species, and provides a basis for gene expression studies of Atlantic cod ES cells.</p

Estimating the prevalence and burden of major disorders of the brain in Nepal: methodology of a nationwide population-based study

BACKGROUND: The major disorders of the brain (MDBs), in terms of their prevalence and the burdens of ill health, disability and financial cost that they impose on individuals and society, are headache, depression and anxiety. No population-based studies have been conducted in Nepal. AIM: Our purpose was to assess the prevalence and burden attributable to MDBs in Nepal in order to inform health policy. Here we report the methodology. METHODS: The unusual sociocultural diversity and extreme geographical variation of the country required adaptation of standard methodology. We ran pre-pilot and pilot studies before embarking on the main study. The study design was cross-sectional. The population of interest were adults aged 18–65 years who were Nepali speaking and living in Nepal. We selected, employed and trained groups of interviewers to visit randomly selected households by cold-calling. Households were selected from 15 representative districts out of 75 in the country through multistage cluster sampling. One participant was selected randomly from each household. We used structured questionnaires (the HARDSHIP questionnaire, Hospital Anxiety and Depression Scale, and Eysenck Personality Questionnaire -Neuroticism), culturally adapted and translated into Nepali. We recorded blood pressure, weight, height and waist circumference, and altitude of each household. We implemented various quality-assurances measures. RESULTS: We completed the survey in one month, prior to onset of the monsoon. Among 2,210 selected households, all were contacted, 2,109 were eligible for the study and, from these, 2,100 adults participated. The participation rate was 99.6%. CONCLUSION: Standard methodology was successfully applied in Nepal, with some adaptations. The sociocultural and extraordinary geographic diversity were challenging, but did not require us to compromise the scientific quality of the study

Oestrogen receptor positive breast cancer metastasis to bone: inhibition by targeting the bone microenvironment in vivo

Clinical trials have shown that adjuvant Zoledronic acid (ZOL) reduces the development of bone metastases irrespective of ER status. However, post-menopausal patients show anti-tumour benefit with ZOL whereas pre-menopausal patients do not. Here we have developed in vivo models of spontaneous ER+ve breast cancer metastasis to bone and investigated the effects of ZOL and oestrogen on tumour cell dissemination and growth. ER+ve (MCF7, T47D) or ER−ve (MDA-MB-231) cells were administered by inter-mammary or inter-cardiac injection into female nude mice ± estradiol. Mice were administered saline or 100 μg/kg ZOL weekly. Tumour growth, dissemination of tumour cells in blood, bone and bone turnover were monitored by luciferase imaging, histology, flow cytometry, two-photon microscopy, micro-CT and TRAP/P1NP ELISA. Estradiol induced metastasis of ER+ve cells to bone in 80–100 % of animals whereas bone metastases from ER−ve cells were unaffected. Administration of ZOL had no effect on tumour growth in the fat pad but significantly inhibited dissemination of ER+ve tumour cells to bone and frequency of bone metastasis. Estradiol and ZOL increased bone volume via different mechanisms: Estradiol increased activity of bone forming osteoblasts whereas administration of ZOL to estradiol supplemented mice decreased osteoclast activity and returned osteoblast activity to levels comparable to that of saline treated mice. ER−ve cells require increased osteoclast activity to grow in bone whereas ER+ve cells do not. Zol does not affect ER+ve tumour growth in soft tissue, however, inhibition of bone turnover by ZOL reduced dissemination and growth of ER+ve breast cancer cells in bone

Transcriptomic profiling reveals novel candidate genes and signalling programs in breast cancer quiescence and dormancy

Metastatic recurrence, the major cause of breast cancer mortality, is driven by reactivation of dormant disseminated tumour cells that are defined by mitotic quiescence and chemoresistance. The molecular mechanisms underpinning mitotic quiescence in cancer are poorly understood, severely limiting the development of novel therapies for removal of residual, metastasis-initiating tumour cells. Here, we present a molecular portrait of the quiescent breast cancer cell transcriptome across the four main breast cancer sub-types (luminal, HER2-enriched, basal-like and claudin-low) and identify a novel quiescence-associated 22-gene signature using an established lipophilic-dye (Vybrant® DiD) retention model and whole-transcriptomic profiling (mRNA-Seq). Using functional association network analysis, we elucidate the molecular interactors of these signature genes. We then go on to demonstrate that our novel 22-gene signature strongly correlates with low tumoural proliferative activity, and with dormant disease and late metastatic recurrence (≥5 years after primary tumour diagnosis) in metastatic breast cancer in multiple clinical cohorts. These genes may govern the formation and persistence of disseminated tumour cell populations responsible for breast cancer recurrence, and therefore represent prospective novel candidates to inform future development of therapeutic strategies to target disseminated tumour cells in breast cancer, eliminate minimal residual disease and prevent metastatic recurrence

The structure of the ternary Eg5–ADP–ispinesib complex

The human kinesin Eg5 is responsible for bipolar spindle formation during early mitosis. Inhibition of Eg5 triggers the formation of monoastral spindles, leading to mitotic arrest that eventually causes apoptosis. There is increasing evidence that Eg5 constitutes a potential drug target for the development of cancer chemotherapeutics. The most advanced Eg5-targeting agent is ispinesib, which exhibits potent antitumour activity and is currently in multiple phase II clinical trials. In this study, the crystal structure of the Eg5 motor domain in complex with ispinesib, supported by kinetic and thermodynamic binding data, is reported. Ispinesib occupies the same induced-fit pocket in Eg5 as other allosteric inhibitors, making extensive hydrophobic interactions with the protein. The data for the Eg5-ADP-ispinesib complex suffered from pseudo-merohedral twinning and revealed translational noncrystallographic symmetry, leading to challenges in data processing, space-group assignment and structure solution as well as in refinement. These complications may explain the lack of available structural information for this important agent and its analogues. The present structure represents the best interpretation of these data based on extensive data-reduction, structure-solution and refinement trials

Reduced levels of Ago2 expression result in increased siRNA competition in mammalian cells

Administration of small interfering RNAs (siRNAs) leads to degradation of specific mRNAs utilizing the cellular RNA interference (RNAi) machinery. It has been demonstrated that co-administration of siRNAs may lead to attenuation of activity of one of the siRNAs. Utilizing antisense and siRNA-mediated RNA-induced silencing complex (RISC) gene reduction we show that siRNA competition is correlated with differences in the cellular expression levels of Ago2, while levels of other RISC proteins have no effect on competition. We also show that under certain conditions siRNA competition rather than reduction of cellular RISC levels may be responsible for apparent reduction in siRNA activity. Furthermore, exploiting siRNA competition, we show that the RISC pathway loads and results in detectable cleavage of the target RNA in ∼2 h after transfection. The RISC pathway is also capable of being reloaded even in the absence of new protein synthesis. RISC reloading and subsequent induction of detectable cleavage of a new target RNA, requires about 9–12 h following the initial transfection